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Techniques and Strategies in Drug Design and Discovery

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (20 June 2023) | Viewed by 18953

Special Issue Editor

Special Issue Information

Dear Colleagues,

Drug discovery is a very complex and difficult process that involves finding and developing new therapeutic entities. In recent years, the methodology behind drug discovery has rapidly evolved and comprises a plethora of paradigms and techniques, but there remains no perfect algorithm for guaranteed success. Despite considerable research, fortunate discoveries and the incredible intuition, inspiration, and creativity of researchers still play a vitally important role in the field of drug discovery, which remains popular among many scientists. Novel approaches and innovations are needed to address the dominant challenge of cost efficiency.

This Special Issue aims to provide a wide and diverse platform for researchers to present their recent efforts to improve current methodologies in order to find new molecular entities. This Special Issue focuses on presenting innovative research as well as reviews of current practices involving all aspects of drug discovery and drug development.

Prof. Dr. George Mihai Nitulescu
Guest Editor

Manuscript Submission Information

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Keywords

  • drug discovery
  • drug development
  • target identification
  • computational drug design
  • structure-based drug design
  • ligand-based drug design

Published Papers (11 papers)

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Editorial

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3 pages, 179 KiB  
Editorial
Techniques and Strategies in Drug Design and Discovery
Int. J. Mol. Sci. 2024, 25(3), 1364; https://doi.org/10.3390/ijms25031364 - 23 Jan 2024
Viewed by 437
Abstract
The process of drug discovery constitutes a highly intricate and formidable undertaking, encompassing the identification and advancement of novel therapeutic entities [...] Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)

Research

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22 pages, 5460 KiB  
Article
Synthesis of 1,3,4-Thiadiazole Derivatives and Their Anticancer Evaluation
Int. J. Mol. Sci. 2023, 24(24), 17476; https://doi.org/10.3390/ijms242417476 - 14 Dec 2023
Cited by 1 | Viewed by 577
Abstract
Thiadiazole derivatives have garnered significant attention in the field of medicinal chemistry due to their diverse pharmacological activities, including anticancer properties. This article presents the synthesis of a series of thiadiazole derivatives and investigates their chemical characterization and potential anticancer effects on various [...] Read more.
Thiadiazole derivatives have garnered significant attention in the field of medicinal chemistry due to their diverse pharmacological activities, including anticancer properties. This article presents the synthesis of a series of thiadiazole derivatives and investigates their chemical characterization and potential anticancer effects on various cell lines. The results of the nuclear magnetic resonance (NMR) analyses confirmed the successful formation of the target compounds. The anticancer potential was evaluated through in silico and in vitro cell-based assays using LoVo and MCF-7 cancer lines. The assays included cell viability, proliferation, apoptosis, and cell cycle analysis to assess the compounds’ effects on cancer cell growth and survival. Daphnia magna was used as an invertebrate model for the toxicity evaluation of the compounds. The results revealed promising anticancer activity for several of the synthesized derivatives, suggesting their potential as lead compounds for further drug development. The novel compound 2g, 5-[2-(benzenesulfonylmethyl)phenyl]-1,3,4-thiadiazol-2-amine, demonstrated good anti-proliferative effects, exhibiting an IC50 value of 2.44 µM against LoVo and 23.29 µM against MCF-7 after a 48-h incubation and little toxic effects in the Daphnia test. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)
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20 pages, 2764 KiB  
Article
AMMVF-DTI: A Novel Model Predicting Drug–Target Interactions Based on Attention Mechanism and Multi-View Fusion
Int. J. Mol. Sci. 2023, 24(18), 14142; https://doi.org/10.3390/ijms241814142 - 15 Sep 2023
Cited by 2 | Viewed by 1047
Abstract
Accurate identification of potential drug–target interactions (DTIs) is a crucial task in drug development and repositioning. Despite the remarkable progress achieved in recent years, improving the performance of DTI prediction still presents significant challenges. In this study, we propose a novel end-to-end deep [...] Read more.
Accurate identification of potential drug–target interactions (DTIs) is a crucial task in drug development and repositioning. Despite the remarkable progress achieved in recent years, improving the performance of DTI prediction still presents significant challenges. In this study, we propose a novel end-to-end deep learning model called AMMVF-DTI (attention mechanism and multi-view fusion), which leverages a multi-head self-attention mechanism to explore varying degrees of interaction between drugs and target proteins. More importantly, AMMVF-DTI extracts interactive features between drugs and proteins from both node-level and graph-level embeddings, enabling a more effective modeling of DTIs. This advantage is generally lacking in existing DTI prediction models. Consequently, when compared to many of the start-of-the-art methods, AMMVF-DTI demonstrated excellent performance on the human, C. elegans, and DrugBank baseline datasets, which can be attributed to its ability to incorporate interactive information and mine features from both local and global structures. The results from additional ablation experiments also confirmed the importance of each module in our AMMVF-DTI model. Finally, a case study is presented utilizing our model for COVID-19-related DTI prediction. We believe the AMMVF-DTI model can not only achieve reasonable accuracy in DTI prediction, but also provide insights into the understanding of potential interactions between drugs and targets. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)
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20 pages, 3186 KiB  
Article
Atezolizumab Induces Necroptosis and Contributes to Hepatotoxicity of Human Hepatocytes
Int. J. Mol. Sci. 2023, 24(14), 11694; https://doi.org/10.3390/ijms241411694 - 20 Jul 2023
Cited by 1 | Viewed by 1127
Abstract
Atezolizumab is an immune checkpoint inhibitor (ICI) targeting PD-L1 for treatment of solid malignancies. Immune checkpoints control the immune tolerance, and the adverse events such as hepatotoxicity induced by ICIs are often considered as an immune-related adverse event (irAE). However, PD-L1 is also [...] Read more.
Atezolizumab is an immune checkpoint inhibitor (ICI) targeting PD-L1 for treatment of solid malignancies. Immune checkpoints control the immune tolerance, and the adverse events such as hepatotoxicity induced by ICIs are often considered as an immune-related adverse event (irAE). However, PD-L1 is also highly expressed in normal tissues, e.g., hepatocytes. It is still not clear whether, targeting PD-L1 on hepatocytes, the atezolizumab may cause damage to liver cells contributing to hepatotoxicity. Here, we reveal a novel mechanism by which the atezolizumab induces hepatotoxicity in human hepatocytes. We find that the atezolizumab treatment increases a release of LDH in the cell culture medium of human hepatocytes (human primary hepatocytes and THLE-2 cells), decreases cell viability, and inhibits the THLE-2 and THLE-3 cell growth. We demonstrate that both the atezolizumab and the conditioned medium (T-CM) derived from activated T cells can induce necroptosis of the THLE-2 cells, which is underscored by the fact that the atezolizumab and T-CM enhance the phosphorylation of RIP3 and MLKL proteins. Furthermore, we also show that necrostatin-1, a necrosome inhibitor, decreases the amount of phosphorylated RIP3 induced by the atezolizumab, resulting in a reduced LDH release in the culture media of the THLE-2 cells. This finding is further supported by the data that GSK872 (a RIP3 inhibitor) significantly reduced the atezolizumab-induced LDH release. Taken together, our data indicate that the atezolizumab induces PD-L1-mediated necrosome formation, contributing to hepatotoxicity in PD-L1+-human hepatocytes. This study provides the molecular basis of the atezolizumab-induced hepatotoxicity and opens a new avenue for developing a novel therapeutic approach to reducing hepatotoxicity induced by ICIs. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)
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27 pages, 4562 KiB  
Article
Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller Streptomyces lunaelactis MM109T
Int. J. Mol. Sci. 2023, 24(2), 1114; https://doi.org/10.3390/ijms24021114 - 06 Jan 2023
Cited by 7 | Viewed by 3442
Abstract
Streptomyces lunaelactis strains have been isolated from moonmilk deposits, which are calcium carbonate speleothems used for centuries in traditional medicine for their antimicrobial properties. Genome mining revealed that these strains are a remarkable example of a Streptomyces species with huge heterogeneity regarding their [...] Read more.
Streptomyces lunaelactis strains have been isolated from moonmilk deposits, which are calcium carbonate speleothems used for centuries in traditional medicine for their antimicrobial properties. Genome mining revealed that these strains are a remarkable example of a Streptomyces species with huge heterogeneity regarding their content in biosynthetic gene clusters (BGCs) for specialized metabolite production. BGC 28a is one of the cryptic BGCs that is only carried by a subgroup of S. lunaelactis strains for which in silico analysis predicted the production of nonribosomal peptide antibiotics containing the non-proteogenic amino acid piperazic acid (Piz). Comparative metabolomics of culture extracts of S. lunaelactis strains either holding or not holding BGC 28a combined with MS/MS-guided peptidogenomics and 1H/13C NMR allowed us to identify the cyclic hexapeptide with the amino acid sequence (D-Phe)-(L-HO-Ile)-(D-Piz)-(L-Piz)-(D-Piz)-(L-Piz), called lunaemycin A, as the main compound synthesized by BGC 28a. Molecular networking further identified 18 additional lunaemycins, with 14 of them having their structure elucidated by HRMS/MS. Antimicrobial assays demonstrated a significant bactericidal activity of lunaemycins against Gram-positive bacteria, including multi-drug resistant clinical isolates. Our work demonstrates how an accurate in silico analysis of a cryptic BGC can highly facilitate the identification, the structural elucidation, and the bioactivity of its associated specialized metabolites. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)
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14 pages, 2824 KiB  
Article
Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors
Int. J. Mol. Sci. 2022, 23(24), 16169; https://doi.org/10.3390/ijms232416169 - 18 Dec 2022
Cited by 2 | Viewed by 1753
Abstract
Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid the reduced efficacy of therapy have been explored, including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary [...] Read more.
Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid the reduced efficacy of therapy have been explored, including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for the survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here the structure-activity relationship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase, and the isopropyl group at position 7 substantially increased the selectivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piperazin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses, including the suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)
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16 pages, 3147 KiB  
Article
A Pyrazolate Osmium(VI) Nitride Exhibits Anticancer Activity through Modulating Protein Homeostasis in HepG2 Cells
Int. J. Mol. Sci. 2022, 23(21), 12779; https://doi.org/10.3390/ijms232112779 - 24 Oct 2022
Cited by 3 | Viewed by 1389
Abstract
Interest in the third-row transition metal osmium and its compounds as potential anticancer agents has grown in recent years. Here, we synthesized the osmium(VI) nitrido complex Na[OsVI(N)(tpm)2] (tpm = [5-(Thien-2-yl)-1H-pyrazol-3-yl]methanol), which exhibited a greater inhibitory effect on the cell [...] Read more.
Interest in the third-row transition metal osmium and its compounds as potential anticancer agents has grown in recent years. Here, we synthesized the osmium(VI) nitrido complex Na[OsVI(N)(tpm)2] (tpm = [5-(Thien-2-yl)-1H-pyrazol-3-yl]methanol), which exhibited a greater inhibitory effect on the cell viabilities of the cervical, ovarian, and breast cancer cell lines compared with cisplatin. Proteomics analysis revealed that Na[OsVI(N)(tpm)2] modulates the expression of protein-transportation-associated, DNA-metabolism-associated, and oxidative-stress-associated proteins in HepG2 cells. Perturbation of protein expression activity by the complex in cancer cells affects the functions of the mitochondria, resulting in high levels of cellular oxidative stress and low rates of cell survival. Moreover, it caused G2/M phase cell cycle arrest and caspase-mediated apoptosis of HepG2 cells. This study reveals a new high-valent osmium complex as an anticancer agent candidate modulating protein homeostasis. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)
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12 pages, 3372 KiB  
Article
CSatDTA: Prediction of Drug–Target Binding Affinity Using Convolution Model with Self-Attention
Int. J. Mol. Sci. 2022, 23(15), 8453; https://doi.org/10.3390/ijms23158453 - 30 Jul 2022
Cited by 11 | Viewed by 2081
Abstract
Drug discovery, which aids to identify potential novel treatments, entails a broad range of fields of science, including chemistry, pharmacology, and biology. In the early stages of drug development, predicting drug–target affinity is crucial. The proposed model, the prediction of drug–target affinity using [...] Read more.
Drug discovery, which aids to identify potential novel treatments, entails a broad range of fields of science, including chemistry, pharmacology, and biology. In the early stages of drug development, predicting drug–target affinity is crucial. The proposed model, the prediction of drug–target affinity using a convolution model with self-attention (CSatDTA), applies convolution-based self-attention mechanisms to the molecular drug and target sequences to predict drug–target affinity (DTA) effectively, unlike previous convolution methods, which exhibit significant limitations related to this aspect. The convolutional neural network (CNN) only works on a particular region of information, excluding comprehensive details. Self-attention, on the other hand, is a relatively recent technique for capturing long-range interactions that has been used primarily in sequence modeling tasks. The results of comparative experiments show that CSatDTA surpasses previous sequence-based or other approaches and has outstanding retention abilities. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)
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Review

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27 pages, 4477 KiB  
Review
Target Identification in Anti-Tuberculosis Drug Discovery
Int. J. Mol. Sci. 2023, 24(13), 10482; https://doi.org/10.3390/ijms241310482 - 22 Jun 2023
Cited by 3 | Viewed by 2119
Abstract
Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is [...] Read more.
Mycobacterium tuberculosis (Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance, and uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation. While the complete genome sequence of Mtb has been determined and several potential protein targets have been validated, the lack of adequate models for in vitro and in vivo studies is a limiting factor in TB drug discovery programs. In current therapeutic regimens, less than 0.5% of bacterial proteins are targeted during the biosynthesis of the cell wall and the energetic metabolism of two of the most important processes exploited for TB chemotherapeutics. This review provides an overview on the current challenges in TB drug discovery and emerging Mtb druggable proteins, and explains how chemical probes for protein profiling enabled the identification of new targets and biomarkers, paving the way to disruptive therapeutic regimens and diagnostic tools. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)
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52 pages, 10302 KiB  
Review
Hunting for Novel Routes in Anticancer Drug Discovery: Peptides against Sam-Sam Interactions
Int. J. Mol. Sci. 2022, 23(18), 10397; https://doi.org/10.3390/ijms231810397 - 08 Sep 2022
Cited by 5 | Viewed by 1800
Abstract
Among the diverse protein binding modules, Sam (Sterile alpha motif) domains attract attention due to their versatility. They are present in different organisms and play many functions in physiological and pathological processes by binding multiple partners. The EphA2 receptor contains a Sam domain [...] Read more.
Among the diverse protein binding modules, Sam (Sterile alpha motif) domains attract attention due to their versatility. They are present in different organisms and play many functions in physiological and pathological processes by binding multiple partners. The EphA2 receptor contains a Sam domain at the C-terminus (EphA2-Sam) that is able to engage protein regulators of receptor stability (including the lipid phosphatase Ship2 and the adaptor Odin). Ship2 and Odin are recruited by EphA2-Sam through heterotypic Sam-Sam interactions. Ship2 decreases EphA2 endocytosis and consequent degradation, producing chiefly pro-oncogenic outcomes in a cellular milieu. Odin, through its Sam domains, contributes to receptor stability by possibly interfering with ubiquitination. As EphA2 is upregulated in many types of tumors, peptide inhibitors of Sam-Sam interactions by hindering receptor stability could function as anticancer therapeutics. This review describes EphA2-Sam and its interactome from a structural and functional perspective. The diverse design strategies that have thus far been employed to obtain peptides targeting EphA2-mediated Sam-Sam interactions are summarized as well. The generated peptides represent good initial lead compounds, but surely many efforts need to be devoted in the close future to improve interaction affinities towards Sam domains and consequently validate their anticancer properties. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)
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36 pages, 4919 KiB  
Review
Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold—A Short Review of Most Recent Studies 2013–2022
Int. J. Mol. Sci. 2022, 23(16), 8874; https://doi.org/10.3390/ijms23168874 - 09 Aug 2022
Cited by 4 | Viewed by 2069
Abstract
The terminal phenoxy group is a moiety of many drugs in use today. Numerous literature reports indicated its crucial importance for biological activity; thus, it is a privileged scaffold in medicinal chemistry. This review focuses on the latest achievements in the field of [...] Read more.
The terminal phenoxy group is a moiety of many drugs in use today. Numerous literature reports indicated its crucial importance for biological activity; thus, it is a privileged scaffold in medicinal chemistry. This review focuses on the latest achievements in the field of novel potential agents bearing a terminal phenoxy group in 2013–2022. The article provided information on neurological, anticancer, potential lymphoma agent, anti-HIV, antimicrobial, antiparasitic, analgesic, anti-diabetic as well as larvicidal, cholesterol esterase inhibitors, and antithrombotic or agonistic activities towards the adrenergic receptor. Additionally, for selected agents, the Structure–Activity–Relationship (SAR) is also discussed. Thus, this study may help the readers to better understand the nature of the phenoxy group, which will translate into rational drug design and the development of a more efficient drug. To the best of our knowledge, this is the first review devoted to an in-depth analysis of the various activities of compounds bearing terminal phenoxy moiety. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery)
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