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17 pages, 5162 KiB

Open AccessArticle

Development of an Automatic Pipeline for Participation in the CELPP Challenge

by Marina Miñarro-Lleonar, Sergio Ruiz-Carmona, Daniel Alvarez-Garcia, Peter Schmidtke and Xavier Barril

Int. J. Mol. Sci. 2022, 23(9), 4756; https://doi.org/10.3390/ijms23094756 - 26 Apr 2022

Cited by 1 | Viewed by 1885

Abstract

The prediction of how a ligand binds to its target is an essential step for Structure-Based Drug Design (SBDD) methods. Molecular docking is a standard tool to predict the binding mode of a ligand to its macromolecular receptor and to quantify their mutual [...] Read more.

The prediction of how a ligand binds to its target is an essential step for Structure-Based Drug Design (SBDD) methods. Molecular docking is a standard tool to predict the binding mode of a ligand to its macromolecular receptor and to quantify their mutual complementarity, with multiple applications in drug design. However, docking programs do not always find correct solutions, either because they are not sampled or due to inaccuracies in the scoring functions. Quantifying the docking performance in real scenarios is essential to understanding their limitations, managing expectations and guiding future developments. Here, we present a fully automated pipeline for pose prediction validated by participating in the Continuous Evaluation of Ligand Pose Prediction (CELPP) Challenge. Acknowledging the intrinsic limitations of the docking method, we devised a strategy to automatically mine and exploit pre-existing data, defining—whenever possible—empirical restraints to guide the docking process. We prove that the pipeline is able to generate predictions for most of the proposed targets as well as obtain poses with low RMSD values when compared to the crystal structure. All things considered, our pipeline highlights some major challenges in the automatic prediction of protein–ligand complexes, which will be addressed in future versions of the pipeline. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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14 pages, 5215 KiB

Open AccessArticle

Inverse Mixed-Solvent Molecular Dynamics for Visualization of the Residue Interaction Profile of Molecular Probes

by Keisuke Yanagisawa, Ryunosuke Yoshino, Genki Kudo and Takatsugu Hirokawa

Int. J. Mol. Sci. 2022, 23(9), 4749; https://doi.org/10.3390/ijms23094749 - 26 Apr 2022

Viewed by 2189

Abstract

To ensure efficiency in discovery and development, the application of computational technology is essential. Although virtual screening techniques are widely applied in the early stages of drug discovery research, the computational methods used in lead optimization to improve activity and reduce the toxicity [...] Read more.

To ensure efficiency in discovery and development, the application of computational technology is essential. Although virtual screening techniques are widely applied in the early stages of drug discovery research, the computational methods used in lead optimization to improve activity and reduce the toxicity of compounds are still evolving. In this study, we propose a method to construct the residue interaction profile of the chemical structure used in the lead optimization by performing “inverse” mixed-solvent molecular dynamics (MSMD) simulation. Contrary to constructing a protein-based, atom interaction profile, we constructed a probe-based, protein residue interaction profile using MSMD trajectories. It provides us the profile of the preferred protein environments of probes without co-crystallized structures. We assessed the method using three probes: benzamidine, catechol, and benzene. As a result, the residue interaction profile of each probe obtained by MSMD was a reasonable physicochemical description of the general non-covalent interaction. Moreover, comparison with the X-ray structure containing each probe as a ligand shows that the map of the interaction profile matches the arrangement of amino acid residues in the X-ray structure. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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17 pages, 5438 KiB

Open AccessArticle

Identification of Corosolic and Oleanolic Acids as Molecules Antagonizing the Human RORγT Nuclear Receptor Using the Calculated Fingerprints of the Molecular Similarity

by Joanna Pastwińska, Kaja Karaś, Anna Sałkowska, Iwona Karwaciak, Katarzyna Chałaśkiewicz, Błażej A. Wojtczak, Rafał A. Bachorz and Marcin Ratajewski

Int. J. Mol. Sci. 2022, 23(3), 1906; https://doi.org/10.3390/ijms23031906 - 08 Feb 2022

Cited by 6 | Viewed by 2391

Abstract

RORγT is a protein product of the RORC gene belonging to the nuclear receptor subfamily of retinoic-acid-receptor-related orphan receptors (RORs). RORγT is preferentially expressed in Th17 lymphocytes and drives their differentiation from naive CD4+ cells and is involved in the regulation of the [...] Read more.

RORγT is a protein product of the RORC gene belonging to the nuclear receptor subfamily of retinoic-acid-receptor-related orphan receptors (RORs). RORγT is preferentially expressed in Th17 lymphocytes and drives their differentiation from naive CD4+ cells and is involved in the regulation of the expression of numerous Th17-specific cytokines, such as IL-17. Because Th17 cells are implicated in the pathology of autoimmune diseases (e.g., psoriasis, inflammatory bowel disease, multiple sclerosis), RORγT, whose activity is regulated by ligands, has been recognized as a drug target in potential therapies against these diseases. The identification of such ligands is time-consuming and usually requires the screening of chemical libraries. Herein, using a Tanimoto similarity search, we found corosolic acid and other pentacyclic tritepenes in the library we previously screened as compounds highly similar to the RORγT inverse agonist ursolic acid. Furthermore, using gene reporter assays and Th17 lymphocytes, we distinguished compounds that exert stronger biological effects (ursolic, corosolic, and oleanolic acid) from those that are ineffective (asiatic and maslinic acids), providing evidence that such combinatorial methodology (in silico and experimental) might help wet screenings to achieve more accurate results, eliminating false negatives. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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25 pages, 5663 KiB

Open AccessArticle

Identification of Potential Antiviral Inhibitors from Hydroxychloroquine and 1,2,4,5-Tetraoxanes Analogues and Investigation of the Mechanism of Action in SARS-CoV-2

by Ryan S. Ramos, Rosivaldo S. Borges, João S. N. de Souza, Inana F. Araujo, Mariana H. Chaves and Cleydson B. R. Santos

Int. J. Mol. Sci. 2022, 23(3), 1781; https://doi.org/10.3390/ijms23031781 - 04 Feb 2022

Cited by 10 | Viewed by 2629

Abstract

This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used [...] Read more.

This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used for the construction and evaluation of pharmacophoric models. The pharmacophore-based virtual screening was performed on the Molport^® database (~7.9 million compounds) and obtained 313 structures. Additionally, a pharmacokinetic study was developed, obtaining 174 structures with 99% confidence for human intestinal absorption and penetration into the blood–brain barrier (BBB); posteriorly, a study of toxicological properties was realized. Toxicological predictions showed that the selected molecules do not present a risk of hepatotoxicity, carcinogenicity, mutagenicity, and skin irritation. Only 54 structures were selected for molecular docking studies, and five structures showed binding affinity (ΔG) values satisfactory for ACE2 receptors (PDB 6M0J), in which the molecule MolPort-007-913-111 had the best ΔG value of −8.540 Kcal/mol, followed by MolPort-002-693-933 with ΔG = −8.440 Kcal/mol. Theoretical determination of biological activity was realized for 54 structures, and five molecules showed potential protease inhibitors. Additionally, we investigated the Mpro receptor (6M0K) for the five structures via molecular docking, and we confirmed the possible interaction with the target. In parallel, we selected the TopsHits 9 with antiviral potential that evaluated synthetic accessibility for future synthesis studies and in vivo and in vitro tests. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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33 pages, 28637 KiB

Open AccessArticle

Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP₃R) Inhibitors in Cancer

by Humaira Ismatullah and Ishrat Jabeen

Int. J. Mol. Sci. 2021, 22(23), 12993; https://doi.org/10.3390/ijms222312993 - 30 Nov 2021

Cited by 6 | Viewed by 2345

Abstract

Inositol 1, 4, 5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Remodeling Ca²⁺ signals by targeting the downstream effectors is considered an important hallmark in cancer progression. Despite [...] Read more.

Inositol 1, 4, 5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Remodeling Ca²⁺ signals by targeting the downstream effectors is considered an important hallmark in cancer progression. Despite recent structural analyses, no binding hypothesis for antagonists within the IP₃-binding core (IBC) has been proposed yet. Therefore, to elucidate the 3D structural features of IP₃R modulators, we used combined pharmacoinformatic approaches, including ligand-based pharmacophore models and grid-independent molecular descriptor (GRIND)-based models. Our pharmacophore model illuminates the existence of two hydrogen-bond acceptors (2.62 Å and 4.79 Å) and two hydrogen-bond donors (5.56 Å and 7.68 Å), respectively, from a hydrophobic group within the chemical scaffold, which may enhance the liability (IC₅₀) of a compound for IP₃R inhibition. Moreover, our GRIND model (PLS: Q² = 0.70 and R² = 0.72) further strengthens the identified pharmacophore features of IP₃R modulators by probing the presence of complementary hydrogen-bond donor and hydrogen-bond acceptor hotspots at a distance of 7.6–8.0 Å and 6.8–7.2 Å, respectively, from a hydrophobic hotspot at the virtual receptor site (VRS). The identified 3D structural features of IP₃R modulators were used to screen (virtual screening) 735,735 compounds from the ChemBridge database, 265,242 compounds from the National Cancer Institute (NCI) database, and 885 natural compounds from the ZINC database. After the application of filters, four compounds from ChemBridge, one compound from ZINC, and three compounds from NCI were shortlisted as potential hits (antagonists) against IP₃R. The identified hits could further assist in the design and optimization of lead structures for the targeting and remodeling of Ca²⁺ signals in cancer. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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24 pages, 9430 KiB

Open AccessArticle

Natural Products-Based Drug Design against SARS-CoV-2 Mpro 3CLpro

by Rai C. Silva, Humberto F. Freitas, Joaquín M. Campos, Njogu M. Kimani, Carlos H. T. P. Silva, Rosivaldo S. Borges, Samuel S. R. Pita and Cleydson B. R. Santos

Int. J. Mol. Sci. 2021, 22(21), 11739; https://doi.org/10.3390/ijms222111739 - 29 Oct 2021

Cited by 22 | Viewed by 4352

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received global attention due to the serious threat it poses to public health. Since the outbreak in December 2019, millions of people have been affected and its rapid global [...] Read more.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received global attention due to the serious threat it poses to public health. Since the outbreak in December 2019, millions of people have been affected and its rapid global spread has led to an upsurge in the search for treatment. To discover hit compounds that can be used alone or in combination with repositioned drugs, we first analyzed the pharmacokinetic and toxicological properties of natural products from Brazil’s semiarid region. After, we analyzed the site prediction and druggability of the SARS-CoV-2 main protease (Mpro), followed by docking and molecular dynamics simulation. The best SARS-CoV-2 Mpro complexes revealed that other sites were accessed, confirming that our approach could be employed as a suitable starting protocol for ligand prioritization, reinforcing the importance of catalytic cysteine-histidine residues and providing new structural data that could increase the antiviral development mainly against SARS-CoV-2. Here, we selected 10 molecules that could be in vitro assayed in response to COVID-19. Two compounds (b01 and b02) suggest a better potential for interaction with SARS-CoV-2 Mpro and could be further studied. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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15 pages, 3483 KiB

Open AccessArticle

Anti-Oxidation and Anti-Inflammatory Potency Evaluation of Ferulic Acid Derivatives Obtained through Virtual Screening

by Yuqi Shi, Xuelian Chen, Shaojia Qiang, Jie Su and Jiazhong Li

Int. J. Mol. Sci. 2021, 22(21), 11305; https://doi.org/10.3390/ijms222111305 - 20 Oct 2021

Cited by 16 | Viewed by 2982

Abstract

Various factors such as ultraviolet rays can cause a continuous threat to our skin, resulting in inflammation or oxidation problems. Ferulic acid (FA), with certain antioxidant and anti-inflammatory properties, is widely used in many cosmetics, even used to treat various diseases in the [...] Read more.

Various factors such as ultraviolet rays can cause a continuous threat to our skin, resulting in inflammation or oxidation problems. Ferulic acid (FA), with certain antioxidant and anti-inflammatory properties, is widely used in many cosmetics, even used to treat various diseases in the clinic. In this study, the FA structural skeleton was used to search for FA derivatives. Then, molecular docking, the rule of five, and Veber rules were performed to virtually screen compounds that can bind to proteins with a good drug likeness. DPPH and ABTS were used to evaluate their antioxidant potency and an MTT assay was employed to investigate the toxicities of the compounds, while Griess Reaction System and ELISA were used to judge the concentration variations of NO and different inflammatory factors (TNF-α, IL-1β, and IL-6). Western blotting featured nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression levels. The trend of the intracellular changes of reactive oxygen species (ROS) was detected by the DCFH-DA method and fluorescence staining. As a result, we found that the ferulic acid derivative S-52372 not only had certain scavenging effects on free radicals in biochemical experiments, but also prevented inflammation and oxidative stress in LPS-stimulated RAW264.7 cells in the cellular environment; intracellular ROS and inflammatory mediators, including iNOS, COX-2, TNF-α, and IL-6, were also suppressed. In a computer prediction, S-52372 owned better water solubility and lower toxicity than FA. This compound deserves further research to find an ideal FA derivative. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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26 pages, 6397 KiB

Open AccessArticle

Discovery and Validation of Lmj_04_BRCT Domain, a Novel Therapeutic Target: Identification of Candidate Drugs for Leishmaniasis

by José Peña-Guerrero, Celia Fernández-Rubio, Aroia Burguete-Mikeo, Rima El-Dirany, Alfonso T. García-Sosa and Paul Nguewa

Int. J. Mol. Sci. 2021, 22(19), 10493; https://doi.org/10.3390/ijms221910493 - 28 Sep 2021

Cited by 10 | Viewed by 2497

Abstract

Since many of the currently available antileishmanial treatments exhibit toxicity, low effectiveness, and resistance, search and validation of new therapeutic targets allowing the development of innovative drugs have become a worldwide priority. This work presents a structure-based drug discovery strategy to validate the [...] Read more.

Since many of the currently available antileishmanial treatments exhibit toxicity, low effectiveness, and resistance, search and validation of new therapeutic targets allowing the development of innovative drugs have become a worldwide priority. This work presents a structure-based drug discovery strategy to validate the Lmj_04_BRCT domain as a novel therapeutic target in Leishmania spp. The structure of this domain was explored using homology modeling, virtual screening, and molecular dynamics studies. Candidate compounds were validated in vitro using promastigotes of Leishmania major, L. amazonensis, and L. infantum, as well as primary mouse macrophages infected with L. major. The novel inhibitor CPE2 emerged as the most active of a group of compounds against Leishmania, being able to significantly reduce the viability of promastigotes. CPE2 was also active against the intracellular forms of the parasites and significantly reduced parasite burden in murine macrophages without exhibiting toxicity in host cells. Furthermore, L. major promastigotes treated with CPE2 showed significant lower expression levels of several genes (α-tubulin, Cyclin CYCA, and Yip1) related to proliferation and treatment resistance. Our in silico and in vitro studies suggest that the Lmj_04_BRCT domain and its here disclosed inhibitors are new potential therapeutic options against leishmaniasis. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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10 pages, 2229 KiB

Open AccessArticle

Discovery of a Non-Nucleoside SETD2 Methyltransferase Inhibitor against Acute Myeloid Leukemia

by Dávid Bajusz, Zsolt Bognár, Jessica Ebner, Florian Grebien and György M. Keserű

Int. J. Mol. Sci. 2021, 22(18), 10055; https://doi.org/10.3390/ijms221810055 - 17 Sep 2021

Cited by 6 | Viewed by 2725

Abstract

Histone methyltransferases (HMTs) have attracted considerable attention as potential targets for pharmaceutical intervention in various malignant diseases. These enzymes are known for introducing methyl marks at specific locations of histone proteins, creating a complex system that regulates epigenetic control of gene expression and [...] Read more.

Histone methyltransferases (HMTs) have attracted considerable attention as potential targets for pharmaceutical intervention in various malignant diseases. These enzymes are known for introducing methyl marks at specific locations of histone proteins, creating a complex system that regulates epigenetic control of gene expression and cell differentiation. Here, we describe the identification of first-generation cell-permeable non-nucleoside type inhibitors of SETD2, the only mammalian HMT that is able to tri-methylate the K36 residue of histone H3. By generating the epigenetic mark H3K36me3, SETD2 is involved in the progression of acute myeloid leukemia. We developed a structure-based virtual screening protocol that was first validated in retrospective studies. Next, prospective screening was performed on a large library of commercially available compounds. Experimental validation of 22 virtual hits led to the discovery of three compounds that showed dose-dependent inhibition of the enzymatic activity of SETD2. Compound C13 effectively blocked the proliferation of two acute myeloid leukemia (AML) cell lines with MLL rearrangements and led to decreased H3K36me3 levels, prioritizing this chemotype as a viable chemical starting point for drug discovery projects. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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17 pages, 2279 KiB

Open AccessArticle

Exploring the Effect of Structure-Based Scaffold Hopping on the Inhibition of Coxsackievirus A24v Transduction by Pentavalent N-Acetylneuraminic Acid Conjugates

by Emil Johansson, Rémi Caraballo, Daniel L. Hurdiss, Nitesh Mistry, C. David Andersson, Rebecca F. Thompson, Neil A. Ranson, Georg Zocher, Thilo Stehle, Niklas Arnberg and Mikael Elofsson

Int. J. Mol. Sci. 2021, 22(16), 8418; https://doi.org/10.3390/ijms22168418 - 05 Aug 2021

Cited by 2 | Viewed by 2106

Abstract

Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals [...] Read more.

Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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15 pages, 3845 KiB

Open AccessArticle

Mechanistic and Predictive QSAR Analysis of Diverse Molecules to Capture Salient and Hidden Pharmacophores for Anti-Thrombotic Activity

by Magdi E. A. Zaki, Sami A. Al-Hussain, Vijay H. Masand, Manoj K. Sabnani and Abdul Samad

Int. J. Mol. Sci. 2021, 22(15), 8352; https://doi.org/10.3390/ijms22158352 - 03 Aug 2021

Cited by 5 | Viewed by 2231

Abstract

Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful [...] Read more.

Thrombosis is a life-threatening disease with a high mortality rate in many countries. Even though anti-thrombotic drugs are available, their serious side effects compel the search for safer drugs. In search of a safer anti-thrombotic drug, Quantitative Structure-Activity Relationship (QSAR) could be useful to identify crucial pharmacophoric features. The present work is based on a larger data set comprising 1121 diverse compounds to develop a QSAR model having a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The developed six parametric model fulfils the recommended values for internal and external validation along with Y-randomization parameters such as R²_tr = 0.831, Q²_LMO = 0.828, R²_ex = 0.783. The present analysis reveals that anti-thrombotic activity is found to be correlated with concealed structural traits such as positively charged ring carbon atoms, specific combination of aromatic Nitrogen and sp2-hybridized carbon atoms, etc. Thus, the model captured reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with factor Xa. The analysis led to the identification of useful novel pharmacophoric features, which could be used for future optimization of lead compounds. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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Review

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11 pages, 2660 KiB

Open AccessReview

Virtual Combinatorial Chemistry and Pharmacological Screening: A Short Guide to Drug Design

by Beatriz Suay-García, Jose I. Bueso-Bordils, Antonio Falcó, Gerardo M. Antón-Fos and Pedro A. Alemán-López

Int. J. Mol. Sci. 2022, 23(3), 1620; https://doi.org/10.3390/ijms23031620 - 30 Jan 2022

Cited by 14 | Viewed by 3907

Abstract

Traditionally, drug development involved the individual synthesis and biological evaluation of hundreds to thousands of compounds with the intention of highlighting their biological activity, selectivity, and bioavailability, as well as their low toxicity. On average, this process of new drug development involved, in [...] Read more.

Traditionally, drug development involved the individual synthesis and biological evaluation of hundreds to thousands of compounds with the intention of highlighting their biological activity, selectivity, and bioavailability, as well as their low toxicity. On average, this process of new drug development involved, in addition to high economic costs, a period of several years before hopefully finding a drug with suitable characteristics to drive its commercialization. Therefore, the chemical synthesis of new compounds became the limiting step in the process of searching for or optimizing leads for new drug development. This need for large chemical libraries led to the birth of high-throughput synthesis methods and combinatorial chemistry. Virtual combinatorial chemistry is based on the same principle as real chemistry—many different compounds can be generated from a few building blocks at once. The difference lies in its speed, as millions of compounds can be produced in a few seconds. On the other hand, many virtual screening methods, such as QSAR (Quantitative Sturcture-Activity Relationship), pharmacophore models, and molecular docking, have been developed to study these libraries. These models allow for the selection of molecules to be synthesized and tested with a high probability of success. The virtual combinatorial chemistry–virtual screening tandem has become a fundamental tool in the process of searching for and developing a drug, as it allows the process to be accelerated with extraordinary economic savings. Full article

(This article belongs to the Special Issue Drug Design and Virtual Screening)

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