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15 pages, 1610 KiB

Open AccessArticle

De Novo Drug Design Using Transformer-Based Machine Translation and Reinforcement Learning of an Adaptive Monte Carlo Tree Search

by Dony Ang, Cyril Rakovski and Hagop S. Atamian

Pharmaceuticals 2024, 17(2), 161; https://doi.org/10.3390/ph17020161 - 27 Jan 2024

Viewed by 3036

Abstract

The discovery of novel therapeutic compounds through de novo drug design represents a critical challenge in the field of pharmaceutical research. Traditional drug discovery approaches are often resource intensive and time consuming, leading researchers to explore innovative methods that harness the power of [...] Read more.

The discovery of novel therapeutic compounds through de novo drug design represents a critical challenge in the field of pharmaceutical research. Traditional drug discovery approaches are often resource intensive and time consuming, leading researchers to explore innovative methods that harness the power of deep learning and reinforcement learning techniques. Here, we introduce a novel drug design approach called drugAI that leverages the Encoder–Decoder Transformer architecture in tandem with Reinforcement Learning via a Monte Carlo Tree Search (RL-MCTS) to expedite the process of drug discovery while ensuring the production of valid small molecules with drug-like characteristics and strong binding affinities towards their targets. We successfully integrated the Encoder–Decoder Transformer architecture, which generates molecular structures (drugs) from scratch with the RL-MCTS, serving as a reinforcement learning framework. The RL-MCTS combines the exploitation and exploration capabilities of a Monte Carlo Tree Search with the machine translation of a transformer-based Encoder–Decoder model. This dynamic approach allows the model to iteratively refine its drug candidate generation process, ensuring that the generated molecules adhere to essential physicochemical and biological constraints and effectively bind to their targets. The results from drugAI showcase the effectiveness of the proposed approach across various benchmark datasets, demonstrating a significant improvement in both the validity and drug-likeness of the generated compounds, compared to two existing benchmark methods. Moreover, drugAI ensures that the generated molecules exhibit strong binding affinities to their respective targets. In summary, this research highlights the real-world applications of drugAI in drug discovery pipelines, potentially accelerating the identification of promising drug candidates for a wide range of diseases. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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15 pages, 16823 KiB

Open AccessArticle

An Integrated Computational and Experimental Approach to Formulate Tamanu Oil Bigels as Anti-Scarring Agent

by Megha Krishnappa, Sindhu Abraham, Sharon Caroline Furtado, Shwetha Krishnamurthy, Aynul Rifaya, Yahya I. Asiri, Kumarappan Chidambaram and Parasuraman Pavadai

Pharmaceuticals 2024, 17(1), 102; https://doi.org/10.3390/ph17010102 - 11 Jan 2024

Viewed by 862

Abstract

Tamanu oil has traditionally been used to treat various skin problems. The oil has wound-healing and skin-regenerating capabilities and encourages the growth of new skin cells, all of which are helpful for fading scars and hyperpigmentation, as well as promoting an all-around glow. [...] Read more.

Tamanu oil has traditionally been used to treat various skin problems. The oil has wound-healing and skin-regenerating capabilities and encourages the growth of new skin cells, all of which are helpful for fading scars and hyperpigmentation, as well as promoting an all-around glow. The strong nutty odor and high viscosity are the major disadvantages associated with its application. The aim of this study was to create bigels using tamanu oil for its anti-scarring properties and predict the possible mechanism of action through the help of molecular docking studies. In silico studies were performed to analyze the binding affinity of the protein with the drug, and the anti-scarring activity was established using a full-thickness excision wound model. In silico studies revealed that the components inophyllum C, 4-norlanosta-17(20),24-diene-11,16-diol-21-oic acid, 3-oxo-16,21-lactone, calanolide A, and calophyllolide had docking scores of −11.3 kcal/mol, −11.1 kcal/mol, −9.8 kcal/mol, and −8.6 kcal/mol, respectively, with the cytokine TGF-β1 receptor. Bigels were prepared with tamanu oil ranging from 5 to 20% along with micronized xanthan gum and evaluated for their pH, viscosity, and spreadability. An acute dermal irritation study in rabbits showed no irritation, erythema, eschar, or edema. In vivo excisional wound-healing studies performed on Wistar rats and subsequent histopathological studies showed that bigels had better healing properties when compared to the commercial formulation (Murivenna^TM oil). This study substantiates the wound-healing and scar reduction potential of tamanu oil bigels. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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27 pages, 9569 KiB

Open AccessArticle

Ligand-Based Drug Design of Genipin Derivatives with Cytotoxic Activity against HeLa Cell Line: A Structural and Theoretical Study

by Diana López-López, Rodrigo Said Razo-Hernández, César Millán-Pacheco, Mario Alberto Leyva-Peralta, Omar Aristeo Peña-Morán, Jessica Nayelli Sánchez-Carranza and Verónica Rodríguez-López

Pharmaceuticals 2023, 16(12), 1647; https://doi.org/10.3390/ph16121647 - 23 Nov 2023

Viewed by 882

Abstract

Cervical cancer is a malignant neoplastic disease, mainly associated to HPV infection, with high mortality rates. Among natural products, iridoids have shown different biological activities, including cytotoxic and antitumor effects, in different cancer cell types. Geniposide and its aglycone Genipin have been assessed [...] Read more.

Cervical cancer is a malignant neoplastic disease, mainly associated to HPV infection, with high mortality rates. Among natural products, iridoids have shown different biological activities, including cytotoxic and antitumor effects, in different cancer cell types. Geniposide and its aglycone Genipin have been assessed against different types of cancer. In this work, both iridoids were evaluated against HeLa and three different cervical cancer cell lines. Furthermore, we performed a SAR analysis incorporating 13 iridoids with a high structural similarity to Geniposide and Genipin, also tested in the HeLa cell line and at the same treatment time. Derived from this analysis, we found that the dipole moment (magnitude and direction) is key for their cytotoxic activity in the HeLa cell line. Then, we proceeded to the ligand-based design of new Genipin derivatives through a QSAR model (R² = 87.95 and Q² = 62.33) that incorporates different quantum mechanic molecular descriptor types (

ρ

,

Δ P S A

,

{∆ P o l a r i z a b i l i t y}^{2}

, and

l o g S

). Derived from the ligand-based design, we observed that the presence of an aldehyde or a hydroxymethyl in C4, hydroxyls in C1, C6, and C8, and the lack of the double bond in C7–C8 increased the predicted biological activity of the iridoids. Finally, ten simple iridoids (D9, D107, D35, D36, D55, D56, D58, D60, D61, and D62) are proposed as potential cytotoxic agents against the HeLa cell line based on their predicted IC₅₀ value and electrostatic features. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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18 pages, 3524 KiB

Open AccessArticle

Identification of Potential Multitarget Compounds against Alzheimer’s Disease through Pharmacophore-Based Virtual Screening

by Géssica Oliveira Mendes, Moysés Fagundes de Araújo Neto, Deyse Brito Barbosa, Mayra Ramos do Bomfim, Lorena Silva Matos Andrade, Paulo Batista de Carvalho, Tiago Alves de Oliveira, Daniel Luciano Falkoski, Eduardo Habib Bechelane Maia, Marcelo Siqueira Valle, Laila Cristina Moreira Damázio, Alisson Marques da Silva, Alex Gutterres Taranto and Franco Henrique Andrade Leite

Pharmaceuticals 2023, 16(12), 1645; https://doi.org/10.3390/ph16121645 - 23 Nov 2023

Viewed by 1035

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive loss of cognitive functions, and it is the most prevalent type of dementia worldwide, accounting for 60 to 70% of cases. The pathogenesis of AD seems to involve three main factors: deficiency in [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive loss of cognitive functions, and it is the most prevalent type of dementia worldwide, accounting for 60 to 70% of cases. The pathogenesis of AD seems to involve three main factors: deficiency in cholinergic transmission, formation of extracellular deposits of β-amyloid peptide, and accumulation of deposits of a phosphorylated form of the TAU protein. The currently available drugs are prescribed for symptomatic treatment and present adverse effects such as hepatotoxicity, hypertension, and weight loss. There is urgency in finding new drugs capable of preventing the progress of the disease, controlling the symptoms, and increasing the survival of patients with AD. This study aims to present new multipurpose compounds capable of simultaneously inhibiting acetylcholinesterase (AChE), butyrylcholinesterase (BChE)—responsible for recycling acetylcholine in the synaptic cleft—and beta-secretase 1 (BACE-1)—responsible for the generation of amyloid-β plaques. AChE, BChE, and BACE-1 are currently considered the best targets for the treatment of patients with AD. Virtual hierarchical screening based on a pharmacophoric model for BACE-1 inhibitors and a dual pharmacophoric model for AChE and BChE inhibitors were used to filter 214,446 molecules by QFIT_BACE > 0 and QFIT_DUAL > 56.34. The molecules selected in this first round were subjected to molecular docking studies with the three targets and further evaluated for their physicochemical and toxicological properties. Three structures: ZINC45068352, ZINC03873986, and ZINC71787288 were selected as good fits for the pharmacophore models, with ZINC03873986 being ultimately prioritized for validation through activity testing and synthesis of derivatives for SAR studies. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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20 pages, 4850 KiB

Open AccessArticle

Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives

by Omur Guven, Belgin Sever, Faika Başoğlu-Ünal, Abdulilah Ece, Hiroshi Tateishi, Ryoko Koga, Mohamed O. Radwan, Nefise Demir, Mustafa Can, Mutlu Dilsiz Aytemir, Jun-ichiro Inoue, Masami Otsuka, Mikako Fujita, Halilibrahim Ciftci and Hasan DeMirci

Pharmaceuticals 2023, 16(11), 1608; https://doi.org/10.3390/ph16111608 - 14 Nov 2023

Viewed by 1755

Abstract

Tumor necrosis factor receptor-associated factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system, [...] Read more.

Tumor necrosis factor receptor-associated factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system, and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. TRAF6 is an important therapeutic target for various disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we presented a TRAF6 N-terminal structure determined at the Turkish light source “Turkish DeLight” to be 3.2 Å resolution at cryogenic temperature (PDB ID: 8HZ2). This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research. Separately, we rationally designed numerous new compounds and performed molecular docking studies using this template (PDB ID:8HZ2). According to the results, 10 new compounds formed key interactions with essential residues and zinc ion in the N-terminal region of TRAF6. Molecular dynamic (MD) simulations were performed for 300 ns to evaluate the stability of three docked complexes (compounds 256, 322, and 489). Compounds 256 and 489 was found to possess favorable bindings with TRAF6. These new compounds also showed moderate to good pharmacokinetic profiles, making them potential future drug candidates as TRAF6 inhibitors. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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23 pages, 3503 KiB

Open AccessArticle

Analgesic Activity of 5-Acetamido-2-Hydroxy Benzoic Acid Derivatives and an In-Vivo and In-Silico Analysis of Their Target Interactions

by Cleydson B. R. Santos, Cleison C. Lobato, Sirlene S. B. Ota, Rai C. Silva, Renata C. V. S. Bittencourt, Jofre J. S. Freitas, Elenilze F. B. Ferreira, Marília B. Ferreira, Renata C. Silva, Anderson B. De Lima, Joaquín M. Campos, Rosivaldo S. Borges and José A. H. M. Bittencourt

Pharmaceuticals 2023, 16(11), 1584; https://doi.org/10.3390/ph16111584 - 09 Nov 2023

Viewed by 889

Abstract

The design, synthesis, and evaluation of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are big challenges today. In this work, two 5-acetamido-2-hydroxy benzoic acid derivatives were proposed, increasing the alkyl position (methyl) in an acetamide moiety, and synthesized, [...] Read more.

The design, synthesis, and evaluation of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are big challenges today. In this work, two 5-acetamido-2-hydroxy benzoic acid derivatives were proposed, increasing the alkyl position (methyl) in an acetamide moiety, and synthesized, and their structural elucidation was performed using ¹H NMR and ¹³C NMR. The changes in methyl in larger groups such as phenyl and benzyl aim to increase their selectivity over cyclooxygenase 2 (COX-2). These 5-acetamido-2-hydroxy benzoic acid derivatives were prepared using classic methods of acylation reactions with anhydride or acyl chloride. Pharmacokinetics and toxicological properties were predicted using computational tools, and their binding affinity (kcal/mol) with COX-2 receptors (Mus musculus and Homo sapiens) was analyzed using docking studies (PDB ID 4PH9, 5KIR, 1PXX and 5F1A). An in-silico study showed that 5-acetamido-2-hydroxy benzoic acid derivates have a better bioavailability and binding affinity with the COX-2 receptor, and in-vivo anti-nociceptive activity was investigated by means of a writhing test induced by acetic acid and a hot plate. PS3, at doses of 20 and 50 mg/kg, reduced painful activity by 74% and 75%, respectively, when compared to the control group (20 mg/kg). Regarding the anti-nociceptive activity, the benzyl showed reductions in painful activity when compared to acetaminophen and 5-acetamido-2-hydroxy benzoic acid. However, the proposed derivatives are potentially more active than 5-acetamido-2-hydroxy benzoic acid and they support the design of novel and safer derivative candidates. Consequently, more studies need to be conducted to evaluate the different pharmacological actions, the toxicity of possible metabolites that can be generated, and their potential use in inflammation and pain therapy. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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13 pages, 1980 KiB

Open AccessArticle

Unraveling the Neuroprotective Effect of Natural Bioactive Compounds Involved in the Modulation of Ischemic Stroke by Network Pharmacology

by Juan Carlos Gomez-Verjan, Emmanuel Alejandro Zepeda-Arzate, José Alberto Santiago-de-la-Cruz, Edgar Antonio Estrella-Parra and Nadia Alejandra Rivero-Segura

Pharmaceuticals 2023, 16(10), 1376; https://doi.org/10.3390/ph16101376 - 28 Sep 2023

Viewed by 1193

Abstract

Ischemic stroke (IS) is one of the leading causes of mortality worldwide. It is characterized by the partial or total occlusion of arteries that supply blood to the brain, leading to the death of brain cells. In recent years, natural bioactive compounds (NBCs) [...] Read more.

Ischemic stroke (IS) is one of the leading causes of mortality worldwide. It is characterized by the partial or total occlusion of arteries that supply blood to the brain, leading to the death of brain cells. In recent years, natural bioactive compounds (NBCs) have shown properties that ameliorate the injury after IS and improve the patient’s outcome, which has proven to be a potential therapeutic strategy due to their neuroprotective effects. Hence, in the present study, we use both systems pharmacology and chemoinformatic analyses to identify which NBCs have the most potential to be used against IS in clinics. Our results identify that flavonoids and terpenoids are the most studied NBCs, and, mainly, salidrosides, ginkgolides A, B, C, and K, cordycepin, curcumin, baicalin, resveratrol, fucose, and cannabidiol, target the main pathological processes occurring in IS. However, the medicinal chemistry properties of such compounds demonstrate that only six fulfill such criteria. However, only cordycepin and salidroside possess properties as leader molecules, suggesting that these compounds may be considered in developing novel drugs against IS. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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16 pages, 2062 KiB

Open AccessArticle

Design of β-Keto Esters with Antibacterial Activity: Synthesis, In Vitro Evaluation, and Theoretical Assessment of Their Reactivity and Quorum-Sensing Inhibition Capacity

by Maximiliano Martínez-Cifuentes, Emmanuel Soto-Tapia, Camila Linares-Pipón, Ben Bradshaw, Paulina Valenzuela-Hormazabal, David Ramírez, Patricio Muñoz-Torres and Claudio Parra

Pharmaceuticals 2023, 16(10), 1339; https://doi.org/10.3390/ph16101339 - 22 Sep 2023

Viewed by 820

Abstract

This work proposes the design of β-keto esters as antibacterial compounds. The design was based on the structure of the autoinducer of bacterial quorum sensing, N-(3-oxo-hexanoyl)-l-homoserine lactone (3-oxo-C6-HSL). Eight β-keto ester analogues were synthesised with good yields and were spectroscopically characterised, showing [...] Read more.

This work proposes the design of β-keto esters as antibacterial compounds. The design was based on the structure of the autoinducer of bacterial quorum sensing, N-(3-oxo-hexanoyl)-l-homoserine lactone (3-oxo-C6-HSL). Eight β-keto ester analogues were synthesised with good yields and were spectroscopically characterised, showing that the compounds were only present in their β-keto ester tautomer form. We carried out a computational analysis of the reactivity and ADME (absorption, distribution, metabolism, and excretion) properties of the compounds as well as molecular docking and molecular dynamics calculations with the LasR and LuxS quorum-sensing (QS) proteins, which are involved in bacterial resistance to antibiotics. The results show that all the compounds exhibit reliable ADME properties and that only compound 7 can present electrophile toxicity. The theoretical reactivity study shows that compounds 6 and 8 present a differential local reactivity regarding the rest of the series. Compound 8 presents the most promising potential in terms of its ability to interact with the LasR and LuxS QS proteins efficiently according to its molecular docking and molecular dynamics calculations. An initial in vitro antimicrobial screening was performed against the human pathogenic bacteria Pseudomonas aeruginosa and Staphylococcus aureus as well as the phytopathogenic bacteria Pseudomonas syringae and Agrobacterium tumefaciens. Compounds 6 and 8 exhibit the most promising results in the in vitro antimicrobial screening against the panel of bacteria studied. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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22 pages, 15302 KiB

Open AccessArticle

Molecular Dynamics Simulations of Drug-Conjugated Cell-Penetrating Peptides

by Márton Ivánczi, Balázs Balogh, Loretta Kis and István Mándity

Pharmaceuticals 2023, 16(9), 1251; https://doi.org/10.3390/ph16091251 - 05 Sep 2023

Cited by 1 | Viewed by 1315

Abstract

Cell-penetrating peptides (CPPs) are small peptides capable of translocating through biological membranes carrying various attached cargo into cells and even into the nucleus. They may also participate in transcellular transport. Our in silico study intends to model several peptides and their conjugates. We [...] Read more.

Cell-penetrating peptides (CPPs) are small peptides capable of translocating through biological membranes carrying various attached cargo into cells and even into the nucleus. They may also participate in transcellular transport. Our in silico study intends to model several peptides and their conjugates. We have selected three CPPs with a linear backbone, including penetratin, a naturally occurring oligopeptide; two of its modified sequence analogues (6,14-Phe-penetratin and dodeca-penetratin); and three natural CPPs with a cyclic backbone: Kalata B1, the Sunflower trypsin inhibitor 1 (SFT1), and Momordica cochinchinensis trypsin inhibitor II (MCoTI-II). We have also built conjugates with the small-molecule drug compounds doxorubicin, zidovudine, and rasagiline for each peptide. Molecular dynamics (MD) simulations were carried out with explicit membrane models. The analysis of the trajectories showed that the interaction of penetratin with the membrane led to spectacular rearrangements in the secondary structure of the peptide, while cyclic peptides remained unchanged due to their high conformational stability. Membrane–peptide and membrane–conjugate interactions have been identified and compared. Taking into account well-known examples from the literature, our simulations demonstrated the utility of computational methods for CPP complexes, and they may contribute to a better understanding of the mechanism of penetration, which could serve as the basis for delivering conjugated drug molecules to their intracellular targets. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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20 pages, 9308 KiB

Open AccessArticle

Underlying Mechanisms of Bergenia spp. to Treat Hepatocellular Carcinoma Using an Integrated Network Pharmacology and Molecular Docking Approach

by Shoukat Hussain, Ghulam Mustafa, Sibtain Ahmed and Mohammed Fahad Albeshr

Pharmaceuticals 2023, 16(9), 1239; https://doi.org/10.3390/ph16091239 - 01 Sep 2023

Viewed by 1351

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common and fatal cancer reported, representing 72.5% of malignancies around the world. The majority of HCC incidents have been associated with infections caused by hepatitis B and C viruses. Many first- and second-line conventional drugs, e.g., [...] Read more.

Hepatocellular carcinoma (HCC) is the fifth most common and fatal cancer reported, representing 72.5% of malignancies around the world. The majority of HCC incidents have been associated with infections caused by hepatitis B and C viruses. Many first- and second-line conventional drugs, e.g., sorafenib, cabozantinib, or ramucirumab, have been used for the management of HCC. Despite different combinational therapies, there are still no defined biomarkers for an early stage diagnosis of HCC. The current study evaluated the potential of Bergenia stracheyi, Bergenia ciliata, Bergenia pacumbis, and Bergenia purpurascens, which belong to the family Saxifragaceae, to treat HCC using an integrated network pharmacology and molecular docking approach. Four active phytochemicals were selected based on oral bioavailability (OB) and drug likeness (DL) parameters. The criteria of phytochemical selection were set to OB > 30% and DL > 0.18. Similarly, the gene targets related to Bergenia spp. and the genes related to HCC were retrieved from different databases. The integration of these genes revealed 98 most common overlapping genes, which were mainly interrelated with HCC pathogenesis. Ultimately, the 98 Bergenia-HCC associated genes were used for protein–protein interaction (PPI), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Gene Ontology (GO) enrichment analyses. Finally, the topological analysis revealed the top ten hub genes with maximum degree rank. From the top ten genes, STAT3, MAPK3, and SRC were selected due to their involvement in GO annotation and KEGG pathway. To confirm the network pharmacology results, molecular docking analysis was performed to target STAT3, MAPK3, and SRC receptor proteins. The phytochemical (+)-catechin 3-gallate exhibited a maximum binding score and strong residue interactions with the active amino acids of MAPK3-binding pockets (S-score: −10.2 kcal/mol), SRC (S-score: −8.9 kcal/mol), and STAT3 (S-score: −8.9 kcal/mol) as receptor proteins. (+)-Catechin 3-gallate and β-sitosterol induced a significant reduction in cell viability in HepG2 after 24 h of treatment in a dose-dependent manner. The results of this study explore the potential of (+)-catechin 3-gallate and β-sitosterol, which can be used in the future as potential drug candidates to suppress HCC. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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20 pages, 2399 KiB

Open AccessArticle

Neuroprotective Properties of Oleanolic Acid—Computational-Driven Molecular Research Combined with In Vitro and In Vivo Experiments

by Katarzyna Stępnik, Wirginia Kukula-Koch, Wojciech Plazinski, Magda Rybicka and Kinga Gawel

Pharmaceuticals 2023, 16(9), 1234; https://doi.org/10.3390/ph16091234 - 31 Aug 2023

Viewed by 1060

Abstract

Oleanolic acid (OA), as a ubiquitous compound in the plant kingdom, is studied for both its neuroprotective and neurotoxic properties. The mechanism of acetylcholinesterase (AChE) inhibitory potential of OA is investigated using molecular dynamic simulations (MD) and docking as well as biomimetic tests. [...] Read more.

Oleanolic acid (OA), as a ubiquitous compound in the plant kingdom, is studied for both its neuroprotective and neurotoxic properties. The mechanism of acetylcholinesterase (AChE) inhibitory potential of OA is investigated using molecular dynamic simulations (MD) and docking as well as biomimetic tests. Moreover, the in vitro SH-SY5Y human neuroblastoma cells and the in vivo zebrafish model were used. The inhibitory potential towards the AChE enzyme is examined using the TLC-bioautography assay (the IC₅₀ value is 9.22 μM). The CH-π interactions between the central fragment of the ligand molecule and the aromatic cluster created by the His440, Phe288, Phe290, Phe330, Phe331, Tyr121, Tyr334, Trp84, and Trp279 side chains are observed. The results of the in vitro tests using the SH-SY5Y cells indicate that the viability rate is reduced to 71.5%, 61%, and 43% at the concentrations of 100 µg/mL, 300 µg/mL, and 1000 µg/mL, respectively, after 48 h of incubation, whereas cytotoxicity against the tested cell line with the IC₅₀ value is 714.32 ± 32.40 µg/mL. The in vivo tests on the zebrafish prove that there is no difference between the control and experimental groups regarding the mortality rate and morphology (p > 0.05). Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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41 pages, 11492 KiB

Open AccessArticle

Design, Synthesis, In Silico Studies and In Vitro Evaluation of New Indole- and/or Donepezil-like Hybrids as Multitarget-Directed Agents for Alzheimer’s Disease

by Violina T. Angelova, Borislav Georgiev, Tania Pencheva, Ilza Pajeva, Miroslav Rangelov, Nadezhda Todorova, Dimitrina Zheleva-Dimitrova, Elena Kalcheva-Yovkova, Iva V. Valkova, Nikolay Vassilev, Rositsa Mihaylova, Denitsa Stefanova, Boris Petrov, Yulian Voynikov and Virginia Tzankova

Pharmaceuticals 2023, 16(9), 1194; https://doi.org/10.3390/ph16091194 - 22 Aug 2023

Cited by 1 | Viewed by 1486

Abstract

Alzheimer’s disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone (3a–r) or [...] Read more.

Alzheimer’s disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone (3a–r) or sulfonyl hydrazone (5a–l) fragments were designed, synthesized, and evaluated as multifunctional ligands against AD-related neurodegenerative mechanisms. Two lead compounds (3c and 3d) exhibited a well-balanced multifunctional profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, and FRAP methods, as well as the inhibition of lipid peroxidation in the linoleic acid system. Compound 3n, possessing two indole scaffolds, showed the highest activity against butyrylcholinesterase (BChE) and a high selectivity index (SI = 47.34), as well as a pronounced protective effect in H₂O₂-induced oxidative stress in SH-SY5Y cells. Moreover, compounds 3c, 3d, and 3n showed low neurotoxicity against malignant neuroblastoma cell lines of human (SH-SY5Y) and murine (Neuro-2a) origin, as well as normal murine fibroblast cells (CCL-1) that indicate the in vitro biocompatibility of the experimental compounds. Furthermore, compounds 3c, 3d, and 3n were capable of penetrating the blood–brain barrier (BBB) in the experimental PAMPA-BBB study. The molecular docking showed that compound 3c could act as a ligand to both MT1 and MT2 receptors, as well as to AchE and BchE enzymes. Taken together, those results outline compounds 3c, 3d, and 3n as promising prototypes in the search of innovative compounds for the treatment of AD-associated neurodegeneration with oxidative stress. This study demonstrates that hydrazone derivatives with melatonin and donepezil are appropriate for further development of new AChE/BChE inhibitory agents. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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16 pages, 6108 KiB

Open AccessArticle

Discovery of Potential Noncovalent Inhibitors of Dehydroquinate Dehydratase from Methicillin-Resistant Staphylococcus aureus through Computational-Driven Drug Design

by César Millán-Pacheco, Lluvia Rios-Soto, Noé Corral-Rodríguez, Erick Sierra-Campos, Mónica Valdez-Solana, Alfredo Téllez-Valencia and Claudia Avitia-Domínguez

Pharmaceuticals 2023, 16(8), 1148; https://doi.org/10.3390/ph16081148 - 12 Aug 2023

Cited by 1 | Viewed by 1115

Abstract

Bacteria resistance to antibiotics is a concerning global health problem; in this context, methicillin-resistant Staphylococcus aureus (MRSA) is considered as a high priority by the World Health Organization. Furthermore, patients with a positive result for COVID-19 received early antibiotic treatment, a fact that [...] Read more.

Bacteria resistance to antibiotics is a concerning global health problem; in this context, methicillin-resistant Staphylococcus aureus (MRSA) is considered as a high priority by the World Health Organization. Furthermore, patients with a positive result for COVID-19 received early antibiotic treatment, a fact that potentially encourages the increase in antibiotic resistance. Therefore, there is an urgency to develop new drugs with molecular mechanisms different from those of the actual treatments. In this context, enzymes from the shikimate pathway, a route absent in humans, such as dehydroquinate dehydratase (DHQD), are considered good targets. In this work, a computer-aided drug design strategy, which involved exhaustive virtual screening and molecular dynamics simulations with MM-PBSA analysis, as well as an in silico ADMETox characterization, was performed to find potential noncovalent inhibitors of DHQD from MRSA (SaDHQD). After filtering the 997 million compounds from the ZINC database, 6700 compounds were submitted to an exhaustive virtual screening protocol. From these data, four molecules were selected and characterized (ZINC000005753647 (1), ZINC000001720488 (2), ZINC000082049768 (3), and ZINC000644149506 (4)). The results indicate that the four potential inhibitors interacted with residues important for substrate binding and catalysis, with an estimated binding free energy like that of the enzyme’s substrate. Their ADMETox-predicted properties suggest that all of them support the structural characteristics to be considered good candidates. Therefore, the four compounds reported here are excellent option to be considered for future in vitro studies to design new SaDHQD noncovalent inhibitors and contribute to the search for new drugs against MRSA. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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15 pages, 14933 KiB

Open AccessArticle

Dipeptidyl Peptidase IV Inhibitory Peptides from Chickpea Proteins (Cicer arietinum L.): Pharmacokinetics, Molecular Interactions, and Multi-Bioactivities

by José Antonio Mora-Melgem, Jesús Gilberto Arámburo-Gálvez, Feliznando Isidro Cárdenas-Torres, Jhonatan Gonzalez-Santamaria, Giovanni Isaí Ramírez-Torres, Aldo Alejandro Arvizu-Flores, Oscar Gerardo Figueroa-Salcido and Noé Ontiveros

Pharmaceuticals 2023, 16(8), 1109; https://doi.org/10.3390/ph16081109 - 04 Aug 2023

Cited by 2 | Viewed by 1735

Abstract

Chickpea (Cicer arietinum L.) peptides can inhibit dipeptidyl peptidase IV (DPP-IV), an important type 2 diabetes mellitus therapeutic target. The molecular interactions between the inhibitory peptides and the active site of DPP-IV have not been thoroughly examined, nor have their pharmacokinetic properties. [...] Read more.

Chickpea (Cicer arietinum L.) peptides can inhibit dipeptidyl peptidase IV (DPP-IV), an important type 2 diabetes mellitus therapeutic target. The molecular interactions between the inhibitory peptides and the active site of DPP-IV have not been thoroughly examined, nor have their pharmacokinetic properties. Therefore, the predictions of legumin- and provicilin-derived DPP-IV inhibitory peptides, their molecular interactions with the active site of DPP-IV, and their pharmacokinetic properties were carried out. Ninety-two unique DPP-IV inhibitory peptides were identified. Papain and trypsin were the enzymes with the highest A_E (0.0927) and lowest B_E (6.8625 × 10⁻⁷) values, respectively. Peptide binding energy values ranged from −5.2 to −7.9 kcal/mol. HIS-PHE was the most potent DPP-IV inhibitory peptide and interacts with residues of the active sites S1 (TYR662) and S2 (GLU205/ARG125 (hydrogen bonds: <3.0 Å)), S2 (GLU205/GLU206 (electrostatic interactions: <3.0 Å)), and S2′ pocket (PHE357 (hydrophobic interaction: 4.36 Å)). Most peptides showed optimal absorption (76.09%), bioavailability (89.13%), and were non-toxic (97.8%) stable for gastrointestinal digestion (73.9%). Some peptides (60.86%) could also inhibit ACE-I. Chickpea is a source of non-toxic and bioavailable DPP-IV-inhibitory peptides with dual bioactivity. Studies addressing the potential of chickpea peptides as therapeutic or adjunct agents for treating type 2 diabetes are warranted. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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29 pages, 7116 KiB

Open AccessArticle

Galactoside-Based Molecule Enhanced Antimicrobial Activity through Acyl Moiety Incorporation: Synthesis and In Silico Exploration for Therapeutic Target

by Faez Ahmmed, Samiah Hamad Al-Mijalli, Emad M. Abdallah, Ibrahim H. Eissa, Ferdausi Ali, Ajmal R. Bhat, Joazaizulfazli Jamalis, Taibi Ben Hadda and Sarkar M. A. Kawsar

Pharmaceuticals 2023, 16(7), 998; https://doi.org/10.3390/ph16070998 - 13 Jul 2023

Viewed by 1439

Abstract

In this study, a series of galactoside-based molecules, compounds of methyl β-d-galactopyranoside (MDGP, 1), were selectively acylated using 2-bromobenzoyl chloride to obtain 6-O-(2-bromobenzoyl) substitution products, which were then transformed into 2,3,4-tri-O-6-(2-bromobenzoyl) compounds (2–7 [...] Read more.

In this study, a series of galactoside-based molecules, compounds of methyl β-d-galactopyranoside (MDGP, 1), were selectively acylated using 2-bromobenzoyl chloride to obtain 6-O-(2-bromobenzoyl) substitution products, which were then transformed into 2,3,4-tri-O-6-(2-bromobenzoyl) compounds (2–7) with various nontraditional acyl substituents. The chemical structures of the synthesized analogs were characterized by spectroscopic methods and physicochemical and elemental data analyses. The antimicrobial activities of the compounds against five human pathogenic bacteria and two phyto-fungi were evaluated in vitro and it was found that the acyl moiety-induced synthesized analogs exhibited varying levels of antibacterial activity against different bacteria, with compounds 3 and 6 exhibiting broad-spectrum activity and compounds 2 and 5 exhibiting activity against specific bacteria. Compounds 3 and 6 were tested for MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) based on their activity. The synthesized analogs were also found to have potential as a source of new antibacterial agents, particularly against gram-positive bacteria. The antifungal results suggested that the synthesized analogs could be a potential source of novel antifungal agents. Moreover, cytotoxicity testing revealed that the compounds are less toxic. A structure-activity relationship (SAR) investigation revealed that the lauroyl chain [CH₃(CH₂)₁₀CO-] and the halo-aromatic chain [3(/4)-Cl.C₆H₄CO-] in combination with sugar, had the most potent activity against bacterial and fungal pathogens. Density functional theory (DFT)-calculated thermodynamic and physicochemical parameters, and molecular docking, showed that the synthesized molecule may block dengue virus 1 NS2B/NS3 protease (3L6P). A 150 ns molecular dynamic simulation indicated stable conformation and binding patterns in a stimulating environment. In silico ADMET calculations suggested that the designed (MDGP, 1) had good drug-likeness values. In summary, the newly synthesized MDGP analogs exhibit potential antiviral activity and could serve as a therapeutic target for dengue virus 1 NS2B/NS3 protease. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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19 pages, 8610 KiB

Open AccessArticle

In Silico Development of Novel Benzofuran-1,3,4-Oxadiazoles as Lead Inhibitors of M. tuberculosis Polyketide Synthase 13

by Ali Irfan, Shah Faisal, Ameer Fawad Zahoor, Razia Noreen, Sami A. Al-Hussain, Burak Tuzun, Rakshanda Javaid, Ahmed A. Elhenawy, Magdi E. A. Zaki, Sajjad Ahmad and Magda H. Abdellattif

Pharmaceuticals 2023, 16(6), 829; https://doi.org/10.3390/ph16060829 - 01 Jun 2023

Cited by 6 | Viewed by 2121

Abstract

Benzofuran and 1,3,4-oxadiazole are privileged and versatile heterocyclic pharmacophores which display a broad spectrum of biological and pharmacological therapeutic potential against a wide variety of diseases. This article reports in silico CADD (computer-aided drug design) and molecular hybridization approaches for the evaluation of [...] Read more.

Benzofuran and 1,3,4-oxadiazole are privileged and versatile heterocyclic pharmacophores which display a broad spectrum of biological and pharmacological therapeutic potential against a wide variety of diseases. This article reports in silico CADD (computer-aided drug design) and molecular hybridization approaches for the evaluation of the chemotherapeutic efficacy of 16 S-linked N-phenyl acetamide moiety containing benzofuran-1,3,4-oxadiazole scaffolds BF1–BF16. This virtual screening was carried out to discover and assess the chemotherapeutic efficacy of BF1–BF16 structural motifs as Mycobacterium tuberculosis polyketide synthase 13 (Mtb Pks13) enzyme inhibitors. The CADD study results revealed that the benzofuran clubbed oxadiazole derivatives BF3, BF4, and BF8 showed excellent and remarkably significant binding energies against the Mtb Pks13 enzyme comparable with the standard benzofuran-based TAM-16 inhibitor. The best binding affinity scores were displayed by 1,3,4-oxadiazoles-based benzofuran scaffolds BF3 (−14.23 kcal/mol), BF4 (−14.82 kcal/mol), and BF8 (−14.11 kcal/mol), in comparison to the binding affinity score of the standard reference TAM-16 drug (−14.61 kcal/mol). 2,5-Dimethoxy moiety-based bromobenzofuran-oxadiazole derivative BF4 demonstrated the highest binding affinity score amongst the screened compounds, and was higher than the reference Pks13 inhibitor TAM-16 drug. The bindings of these three leads BF3, BF4, and BF8 were further confirmed by the MM-PBSA investigations in which they also exhibited strong bindings with the Pks13 of Mtb. Moreover, the stability analysis of these benzofuran-1,3,4-oxadiazoles in the active sites of the Pks13 enzyme was achieved through molecular dynamic (MD) simulations at 250 ns virtual simulation time, which indicated that these three in silico predicted bio-potent benzofuran tethered oxadiazole molecules BF3, BF4, and BF8 demonstrated stability with the active site of the Pks13 enzyme. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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19 pages, 2513 KiB

Open AccessArticle

Synthesis, Physicochemical Characterization, Biological Evaluation, In Silico and Molecular Docking Studies of Pd(II) Complexes with P, S-Donor Ligands

by Hizbullah Khan, Muhammad Sirajuddin, Amin Badshah, Sajjad Ahmad, Muhammad Bilal, Syed Muhammad Salman, Ian S. Butler, Tanveer A. Wani and Seema Zargar

Pharmaceuticals 2023, 16(6), 806; https://doi.org/10.3390/ph16060806 - 29 May 2023

Cited by 2 | Viewed by 1347

Abstract

One homoleptic (1) and three heteroleptic (2–4) palladium(II) complexes were synthesized and characterized by various physicochemical techniques, i.e., elemental analysis, FTIR, Raman spectroscopy, ¹H, ¹³C, and ³¹P NMR. Compound 1 was also confirmed by [...] Read more.

One homoleptic (1) and three heteroleptic (2–4) palladium(II) complexes were synthesized and characterized by various physicochemical techniques, i.e., elemental analysis, FTIR, Raman spectroscopy, ¹H, ¹³C, and ³¹P NMR. Compound 1 was also confirmed by single crystal XRD, showing a slightly distorted square planar geometry. The antibacterial results obtained via the agar-well diffusion method for compound 1 were maximum among the screen compounds. All the compounds have shown good to significant antibacterial results against the tested bacterial strains, Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus, except 2 against Klebsiella pneumonia. Similarly, the molecular docking study of compound 3 has shown the best affinity with binding energy scores of −8.6569, −6.5716, and −7.6966 kcal/mol against Escherichia coli, Klebsiella pneumonia, and Staphylococcus aureus, respectively. Compound 2 has exhibited the highest activity (3.67 µM), followed by compound 3 (4.57 µM), 1 (6.94 µM), and 4 (21.7 µM) against the DU145 human prostate cancer cell line using the sulforhodamine B (SRB) method as compared to cisplatin (>200 µM). The highest docking score was obtained for compounds 2 (−7.5148 kcal/mol) and 3 (−7.0343 kcal/mol). Compound 2 shows that the Cl atom of the compound acts as a chain side acceptor for the DR5 receptor residue Asp B218 and the pyridine ring is involved in interaction with the Tyr A50 residue via arene-H, while Compound 3 interacts with the Asp B218 residue via the Cl atom. The physicochemical parameters determined by the SwissADME webserver revealed that no blood-brain barrier (BBB) permeation is predicted for all four compounds, while gastrointestinal absorption is low for compound 1 and high for the rest of the compounds (2–4). As concluding remarks based on the obtained in vitro biological results, the evaluated compounds after in vivo studies might be a good choice for future antibiotics and anticancer agents. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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23 pages, 3166 KiB

Open AccessArticle

Diosgenin and Monohydroxy Spirostanol from Prunus amygdalus var amara Seeds as Potential Suppressors of EGFR and HER2 Tyrosine Kinases: A Computational Approach

by Mohammed Helmy Faris Shalayel, Ghassab M. Al-Mazaideh, Abdulkareem A. Alanezi, Afaf F. Almuqati and Meshal Alotaibi

Pharmaceuticals 2023, 16(5), 704; https://doi.org/10.3390/ph16050704 - 06 May 2023

Cited by 3 | Viewed by 1647

Abstract

Cancer continues to be leading cause of death globally, with nearly 7 million deaths per year. Despite significant progress in cancer research and treatment, there remain several challenges to overcome, including drug resistance, the presence of cancer stem cells, and high interstitial fluid [...] Read more.

Cancer continues to be leading cause of death globally, with nearly 7 million deaths per year. Despite significant progress in cancer research and treatment, there remain several challenges to overcome, including drug resistance, the presence of cancer stem cells, and high interstitial fluid pressure in tumors. To tackle these challenges, targeted therapy, specifically targeting HER2 (Human Epidermal Growth Factor Receptor 2) as well as EGFR (Epidermal Growth Factor Receptor), is considered a promising approach in cancer treatment. In recent years, phytocompounds have gained recognition as a potential source of chemopreventive and chemotherapeutic agents in tumor cancer treatment. Phytocompounds are compounds derived from medicinal plants that have the potential to treat and prevent cancer. This study aimed to investigate phytocompounds from Prunus amygdalus var amara seeds as inhibitors against EGFR and HER2 enzymes using in silico methods. In this study, fourteen phytocompounds were isolated from Prunus amygdalus var amara seeds and subjected to molecular docking studies to determine their ability to bind to EGFR and HER2 enzymes. The results showed that diosgenin and monohydroxy spirostanol exhibited binding energies comparable to those of the reference drugs, tak-285, and lapatinib. Furthermore, the drug-likeness and ADMET predictions, performed using the admetSAR 2.0 web-server tool, suggested that diosgenin and monohydroxy spirostanol have similar safety and ADMET properties as the reference drugs. To get deeper insight into the structural steadiness and flexibility of the complexes formed between these compounds and theEGFR and HER2 proteins, molecular dynamics simulations were performed for 100 ns. The results showed that the hit phytocompounds did not significantly affect the stability of the EGFR and HER2 proteins and were able to form stable interactions with the catalytic binding sites of the proteins. Additionally, the MM-PBSA analysis revealed that the binding free energy estimates for diosgenin and monohydroxy spirostanol is comparable to the reference drug, lapatinib. This study provides evidence that diosgenin and monohydroxy spirostanol may have the potential to act as dual suppressors of EGFR and HER2. Additional in vivo and in vitro research are needed to certify these results and assess their efficacy and safety as cancer therapy agents. The experimental data reported and these results are in agreement. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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20 pages, 11170 KiB

Open AccessArticle

Synthesis, Structural Elucidation and Pharmacological Applications of Cu(II) Heteroleptic Carboxylates

by Shaker Ullah, Muhammad Sirajuddin, Zafran Ullah, Afifa Mushtaq, Saba Naz, Muhammad Zubair, Ali Haider, Saqib Ali, Maciej Kubicki, Tanveer A. Wani, Seema Zargar and Mehboob Ur Rehman

Pharmaceuticals 2023, 16(5), 693; https://doi.org/10.3390/ph16050693 - 03 May 2023

Cited by 5 | Viewed by 1612

Abstract

Six heteroleptic Cu(II) carboxylates (1–6) were prepared by reacting 2-chlorophenyl acetic acid (L¹), 3-chlorophenyl acetic acid (L²), and substituted pyridine (2-cyanopyridine and 2-chlorocyanopyridine). The solid-state behavior of the complexes was described via vibrational [...] Read more.

Six heteroleptic Cu(II) carboxylates (1–6) were prepared by reacting 2-chlorophenyl acetic acid (L¹), 3-chlorophenyl acetic acid (L²), and substituted pyridine (2-cyanopyridine and 2-chlorocyanopyridine). The solid-state behavior of the complexes was described via vibrational spectroscopy (FT-IR), which revealed that the carboxylate moieties adopted different coordination modes around the Cu(II) center. A paddlewheel dinuclear structure with distorted square pyramidal geometry was elucidated from the crystal data for complexes 2 and 5 with substituted pyridine moieties at the axial positions. The presence of irreversible metal-centered oxidation reduction peaks confirms the electroactive nature of the complexes. A relatively higher binding affinity was observed for the interaction of SS-DNA with complexes 2–6 compared to L¹ and L². The findings of the DNA interaction study indicate an intercalative mode of interaction. The maximum inhibition against acetylcholinesterase enzyme was caused for complex 2 (IC₅₀ = 2 µg/mL) compared to the standard drug Glutamine (IC₅₀ = 2.10 µg/mL) while the maximum inhibition was found for butyrylcholinesterase enzyme by complex 4 (IC₅₀ = 3 µg/mL) compared to the standard drug Glutamine (IC₅₀ = 3.40 µg/mL). The findings of the enzymatic activity suggest that the under study compounds have potential for curing of Alzheimer’s disease. Similarly, complexes 2 and 4 possess the maximum inhibition as revealed from the free radical scavenging activity performed against DPPH and H₂O₂. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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18 pages, 8543 KiB

Open AccessArticle

Structure-Based Virtual Screening of Furan-1,3,4-Oxadiazole Tethered N-phenylacetamide Derivatives as Novel Class of hTYR and hTYRP1 Inhibitors

by Ali Irfan, Shah Faisal, Sajjad Ahmad, Sami A. Al-Hussain, Sadia Javed, Ameer Fawad Zahoor, Bushra Parveen and Magdi E. A. Zaki

Pharmaceuticals 2023, 16(3), 344; https://doi.org/10.3390/ph16030344 - 23 Feb 2023

Cited by 9 | Viewed by 1821

Abstract

Human tyrosinase (hTYR) is a key and rate-limiting enzyme along with human tyrosinase-related protein-1 (hTYRP1), which are among the most prominent targets of inhibiting hyper pigmentation and melanoma skin cancer. In the current in-silico computer-aided drug design (CADD) study, the structure-based screening of [...] Read more.

Human tyrosinase (hTYR) is a key and rate-limiting enzyme along with human tyrosinase-related protein-1 (hTYRP1), which are among the most prominent targets of inhibiting hyper pigmentation and melanoma skin cancer. In the current in-silico computer-aided drug design (CADD) study, the structure-based screening of sixteen furan-1,3,4-oxadiazole tethered N-phenylacetamide structural motifs BF1–BF16 was carried out to assess their potential as hTYR and hTYRP1 inhibitors. The results revealed that the structural motifs BF1–BF16 showed higher binding affinities towards hTYR and hTYRP1 than the standard inhibitor kojic acid. The most bioactive lead furan-1,3,4-oxadiazoles BF4 and BF5 displayed stronger binding in affinities (−11.50 kcal/mol and −13.30 kcal/mol) than the standard drug kojic acid against hTYRP1 and hTYR enzymes, respectively. These were further confirmed by MM-GBSA and MM-PBSA binding energy computations. The stability studies involving the molecular dynamics simulations also provided stability insights into the binding of these compounds with the target enzymes, wherein it was found that they remain stable in the active sites during the 100 ns virtual simulation time. Moreover, the ADMET, as well as the medicinal properties of these novel furan-1,3,4-oxadiazole tethered N-phenylacetamide structural hybrids, also showed a good prospect. The excellent in-silico profiling of furan-1,3,4--oxadiazole structural motifs BF4 and BF5 provide a hypothetical gateway to use these compounds as potential hTYRP1 and hTYR inhibitors against melanogenesis. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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19 pages, 5199 KiB

Open AccessArticle

In Silico Screening of Drugs That Target Different Forms of E Protein for Potential Treatment of COVID-19

by Gema Lizbeth Ramírez Salinas, Alejandro López Rincón, Jazmín García Machorro, José Correa Basurto and Marlet Martínez Archundia

Pharmaceuticals 2023, 16(2), 296; https://doi.org/10.3390/ph16020296 - 14 Feb 2023

Cited by 3 | Viewed by 1748

Abstract

Recently the E protein of SARS-CoV-2 has become a very important target in the potential treatment of COVID-19 since it is known to regulate different stages of the viral cycle. There is biochemical evidence that E protein exists in two forms, as monomer [...] Read more.

Recently the E protein of SARS-CoV-2 has become a very important target in the potential treatment of COVID-19 since it is known to regulate different stages of the viral cycle. There is biochemical evidence that E protein exists in two forms, as monomer and homopentamer. An in silico screening analysis was carried out employing 5852 ligands (from Zinc databases), and performing an ADMET analysis, remaining a set of 2155 compounds. Furthermore, docking analysis was performed on specific sites and different forms of the E protein. From this study we could identify that the following ligands showed the highest binding affinity: nilotinib, dutasteride, irinotecan, saquinavir and alectinib. We carried out some molecular dynamics simulations and free energy MM–PBSA calculations of the protein–ligand complexes (with the mentioned ligands). Of worthy interest is that saquinavir, nilotinib and alectinib are also considered as a promising multitarget ligand because it seems to inhibit three targets, which play an important role in the viral cycle. On the other side, saquinavir was shown to be able to bind to E protein both in its monomeric as well as pentameric forms. Finally, further experimental assays are needed to probe our hypothesis derived from in silico studies. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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14 pages, 2745 KiB

Open AccessReview

An Innovative Approach to Address Neurodegenerative Diseases through Kinase-Targeted Therapies: Potential for Designing Covalent Inhibitors

by Swapnil P. Bhujbal and Jung-Mi Hah

Pharmaceuticals 2023, 16(9), 1295; https://doi.org/10.3390/ph16091295 - 13 Sep 2023

Viewed by 1857

Abstract

Owing to the dysregulation of protein kinase activity in various diseases such as cancer and autoimmune, cardiovascular, neurodegenerative, and inflammatory conditions, the protein kinase family has emerged as a crucial drug target in the 21st century. Notably, many kinases have been targeted to [...] Read more.

Owing to the dysregulation of protein kinase activity in various diseases such as cancer and autoimmune, cardiovascular, neurodegenerative, and inflammatory conditions, the protein kinase family has emerged as a crucial drug target in the 21st century. Notably, many kinases have been targeted to address cancer and neurodegenerative diseases using conventional ATP-mimicking kinase inhibitors. Likewise, irreversible covalent inhibitors have also been developed for different types of cancer. The application of covalent modification to target proteins has led to significant advancements in the treatment of cancer. However, while covalent drugs have significantly impacted medical treatment, their potential for neurodegenerative diseases remains largely unexplored. Neurodegenerative diseases present significant risks to brain function, leading to progressive deterioration in sensory, motor, and cognitive abilities. Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and multiple sclerosis (MS) are among the various examples of such disorders. Numerous research groups have already reported insights through reviews and research articles on FDA-approved covalent inhibitors, revealing their mechanisms and the specific covalent warheads that preferentially interact with particular amino acid residues in intricate detail. Hence, in this review, we aim to provide a concise summary of these critical topics. This summary endeavors to guide medicinal chemists in their quest to design covalent inhibitors for protein kinases, specifically targeting neurodegenerative diseases. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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11 pages, 912 KiB

Open AccessReview

The Role of AI in Drug Discovery: Challenges, Opportunities, and Strategies

by Alexandre Blanco-González, Alfonso Cabezón, Alejandro Seco-González, Daniel Conde-Torres, Paula Antelo-Riveiro, Ángel Piñeiro and Rebeca Garcia-Fandino

Pharmaceuticals 2023, 16(6), 891; https://doi.org/10.3390/ph16060891 - 18 Jun 2023

Cited by 52 | Viewed by 19984

Abstract

Artificial intelligence (AI) has the potential to revolutionize the drug discovery process, offering improved efficiency, accuracy, and speed. However, the successful application of AI is dependent on the availability of high-quality data, the addressing of ethical concerns, and the recognition of the limitations [...] Read more.

Artificial intelligence (AI) has the potential to revolutionize the drug discovery process, offering improved efficiency, accuracy, and speed. However, the successful application of AI is dependent on the availability of high-quality data, the addressing of ethical concerns, and the recognition of the limitations of AI-based approaches. In this article, the benefits, challenges, and drawbacks of AI in this field are reviewed, and possible strategies and approaches for overcoming the present obstacles are proposed. The use of data augmentation, explainable AI, and the integration of AI with traditional experimental methods, as well as the potential advantages of AI in pharmaceutical research, are also discussed. Overall, this review highlights the potential of AI in drug discovery and provides insights into the challenges and opportunities for realizing its potential in this field. Note from the human authors: This article was created to test the ability of ChatGPT, a chatbot based on the GPT-3.5 language model, in terms of assisting human authors in writing review articles. The text generated by the AI following our instructions (see Supporting Information) was used as a starting point, and its ability to automatically generate content was evaluated. After conducting a thorough review, the human authors practically rewrote the manuscript, striving to maintain a balance between the original proposal and the scientific criteria. The advantages and limitations of using AI for this purpose are discussed in the last section. Full article

(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)

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