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Computational Methods for Drug Discovery and Design II

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 August 2021) | Viewed by 18224

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Special Issue Editor

Prof. Dr. Julio Caballero

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Guest Editor

Centro de Bioinformática y Simulación Molecular (CBSM), Facultad de Ingeniería, Universidad de Talca, Casilla 747, Talca 3460000, Chile
Interests: molecular modeling; molecular simulations; computational biochemistry; computer-aided drug design; protein kinase inhibitors
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Special Issue Information

Dear Colleagues,

We are pleased to inform you that Molecules will launch the second part of the Special Issue “Computational Methods for Drug Discovery and Design”.

In recent decades, drug design processes have been often assisted by computational methods. Such methods have been crucial to sustaining the current development of medicinal chemistry research. It is rare to see a medicinal chemistry project without the support of computational methods in the fields of pharmaceutical modeling, molecular modeling and simulation, cheminformatics, bioinformatics, computational chemistry, and biochemistry. These methods encompass tools that contribute to the finding of novel drugs or the processing of available information for creating useful knowledge about the interactions between bioactive ligands and their biological targets.

We are seeking original articles, short communications, or review articles focusing on the use of computational methods for drug design processes. Papers employing computational methods available for in silico drug design, such as docking, molecular dynamics, QSAR, pharmacophore modeling, virtual screening, free energy calculations, density functional theory applications, and QM/MM, are welcome. Papers combining both experimental and computational studies are also desired.

Prof. Dr. Julio Caballero
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Molecular modeling
Molecular simulation
Computer-aided drug design
Docking
Molecular dynamics
QSAR
Virtual screening

Related Special Issue

Computational Methods for Drug Discovery and Design in Molecules (13 articles)

Published Papers (7 papers)

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Research

19 pages, 3479 KiB

Open AccessArticle

Engineered Fully Human Single-Chain Monoclonal Antibodies to PIM2 Kinase

by Kanasap Kaewchim, Kittirat Glab-ampai, Kodchakorn Mahasongkram, Monrat Chulanetra, Watee Seesuay, Wanpen Chaicumpa and Nitat Sookrung

Molecules 2021, 26(21), 6436; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216436 - 25 Oct 2021

Cited by 5 | Viewed by 2115

Abstract

Proviral integration site of Moloney virus-2 (PIM2) is overexpressed in multiple human cancer cells and high level is related to poor prognosis; thus, PIM2 kinase is a rational target of anti-cancer therapeutics. Several chemical inhibitors targeting PIMs/PIM2 or their downstream signaling molecules have been developed for treatment of different cancers. However, their off-target toxicity is common in clinical trials, so they could not be advanced to official approval for clinical application. Here, we produced human single-chain antibody fragments (HuscFvs) to PIM2 by using phage display library, which was constructed in a way that a portion of phages in the library carried HuscFvs against human own proteins on their surface with the respective antibody genes in the phage genome. Bacterial derived-recombinant PIM2 (rPIM2) was used as an antigenic bait to fish out the rPIM2-bound phages from the library. Three E. coli clones transfected with the HuscFv genes derived from the rPIM2-bound phages expressed HuscFvs that bound also to native PIM2 from cancer cells. The HuscFvs presumptively interact with the PIM2 at the ATP binding pocket and kinase active loop. They were as effective as small chemical drug inhibitor (AZD1208, which is an ATP competitive inhibitor of all PIM isoforms for ex vivo use) in inhibiting PIM kinase activity. The HuscFvs should be engineered into a cell-penetrating format and tested further towards clinical application as a novel and safe pan-anti-cancer therapeutics. Full article

(This article belongs to the Special Issue Computational Methods for Drug Discovery and Design II)

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19 pages, 41272 KiB

Open AccessArticle

Simulation of the Interactions of Arginine with Wild-Type GALT Enzyme and the Classic Galactosemia-Related Mutant p.Q188R by a Computational Approach

by Anna Verdino, Gaetano D’Urso, Carmen Tammone, Bernardina Scafuri, Lucrezia Catapano and Anna Marabotti

Molecules 2021, 26(19), 6061; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26196061 - 07 Oct 2021

Cited by 2 | Viewed by 2124

Abstract

Classic galactosemia is an inborn error of metabolism associated with mutations that impair the activity and the stability of galactose-1-phosphate uridylyltransferase (GALT), catalyzing the third step in galactose metabolism. To date, no treatments (including dietary galactose deprivation) are able to prevent or alleviate the long-term complications affecting galactosemic patients. Evidence that arginine is able to improve the activity of the human enzyme expressed in a prokaryotic model of classic galactosemia has induced researchers to suppose that this amino acid could act as a pharmacochaperone, but no effects were detected in four galactosemic patients treated with this amino acid. Given that no molecular characterizations of the possible effects of arginine on GALT have been performed, and given that the samples of patients treated with arginine are extremely limited for drawing definitive conclusions at the clinical level, we performed computational simulations in order to predict the interactions (if any) between this amino acid and the enzyme. Our results do not support the possibility that arginine could function as a pharmacochaperone for GALT, but information obtained by this study could be useful for identifying, in the future, possible pharmacochaperones for this enzyme. Full article

(This article belongs to the Special Issue Computational Methods for Drug Discovery and Design II)

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13 pages, 2983 KiB

Open AccessArticle

Analysis of the Structure-Function-Dynamics Relationships of GALT Enzyme and of Its Pathogenic Mutant p.Q188R: A Molecular Dynamics Simulation Study in Different Experimental Conditions

by Anna Verdino, Gaetano D’Urso, Carmen Tammone, Bernardina Scafuri and Anna Marabotti

Molecules 2021, 26(19), 5941; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26195941 - 30 Sep 2021

Cited by 4 | Viewed by 2151

Abstract

The third step of the catabolism of galactose in mammals is catalyzed by the enzyme galactose-1-phosphate uridylyltransferase (GALT), a homodimeric enzyme with two active sites located in the proximity of the intersubunit interface. Mutations of this enzyme are associated to the rare inborn error of metabolism known as classic galactosemia; in particular, the most common mutation, associated with the most severe phenotype, is the one that replaces Gln188 in the active site of the enzyme with Arg (p.Gln188Arg). In the past, and more recently, the structural effects of this mutation were deduced on the static structure of the wild-type human enzyme; however, we feel that a dynamic view of the proteins is necessary to deeply understand their behavior and obtain tips for possible therapeutic interventions. Thus, we performed molecular dynamics simulations of both wild-type and p.Gln188Arg GALT proteins in the absence or in the presence of the substrates in different conditions of temperature. Our results suggest the importance of the intersubunit interactions for a correct activity of this enzyme and can be used as a starting point for the search of drugs able to rescue the activity of this enzyme in galactosemic patients. Full article

(This article belongs to the Special Issue Computational Methods for Drug Discovery and Design II)

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27 pages, 4026 KiB

Open AccessArticle

Force Field Parameters for Fe²⁺₄S²⁻₄ Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies

by Maureen Bilinga Tendwa, Lorna Chebon-Bore, Kevin Lobb, Thommas Mutemi Musyoka and Özlem Tastan Bishop

Molecules 2021, 26(10), 2929; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26102929 - 14 May 2021

Cited by 1 | Viewed by 3399

Abstract

The dimeric dihydropyrimidine dehydrogenase (DPD), metalloenzyme, an adjunct anti-cancer drug target, contains highly specialized 4 × Fe²⁺₄S²⁻₄ clusters per chain. These clusters facilitate the catalysis of the rate-limiting step in the pyrimidine degradation pathway through a harmonized electron transfer cascade that triggers a redox catabolic reaction. In the process, the bulk of the administered 5-fluorouracil (5-FU) cancer drug is inactivated, while a small proportion is activated to nucleic acid antimetabolites. The occurrence of missense mutations in DPD protein within the general population, including those of African descent, has adverse toxicity effects due to altered 5-FU metabolism. Thus, deciphering mutation effects on protein structure and function is vital, especially for precision medicine purposes. We previously proposed combining molecular dynamics (MD) and dynamic residue network (DRN) analysis to decipher the molecular mechanisms of missense mutations in other proteins. However, the presence of Fe²⁺₄S²⁻₄ clusters in DPD poses a challenge for such in silico studies. The existing AMBER force field parameters cannot accurately describe the Fe²⁺ center coordination exhibited by this enzyme. Therefore, this study aimed to derive AMBER force field parameters for DPD enzyme Fe²⁺ centers, using the original Seminario method and the collation features Visual Force Field Derivation Toolkit as a supportive approach. All-atom MD simulations were performed to validate the results. Both approaches generated similar force field parameters, which accurately described the human DPD protein Fe²⁺₄S²⁻₄ cluster architecture. This information is crucial and opens new avenues for in silico cancer pharmacogenomics and drug discovery related research on 5-FU drug efficacy and toxicity issues. Full article

(This article belongs to the Special Issue Computational Methods for Drug Discovery and Design II)

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25 pages, 35011 KiB

Open AccessArticle

Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors

by Conrad V. Simoben, Ehab Ghazy, Patrik Zeyen, Salma Darwish, Matthias Schmidt, Christophe Romier, Dina Robaa and Wolfgang Sippl

Molecules 2021, 26(9), 2584; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092584 - 28 Apr 2021

Cited by 8 | Viewed by 2701

Abstract

Histone-modifying proteins have been identified as promising targets to treat several diseases including cancer and parasitic ailments. In silico methods have been incorporated within a variety of drug discovery programs to facilitate the identification and development of novel lead compounds. In this study, we explore the binding modes of a series of benzhydroxamates derivatives developed as histone deacetylase inhibitors of Schistosoma mansoni histone deacetylase (smHDAC) using molecular docking and binding free energy (BFE) calculations. The developed docking protocol was able to correctly reproduce the experimentally established binding modes of resolved smHDAC8–inhibitor complexes. However, as has been reported in former studies, the obtained docking scores weakly correlate with the experimentally determined activity of the studied inhibitors. Thus, the obtained docking poses were refined and rescored using the Amber software. From the computed protein–inhibitor BFE, different quantitative structure–activity relationship (QSAR) models could be developed and validated using several cross-validation techniques. Some of the generated QSAR models with good correlation could explain up to ~73% variance in activity within the studied training set molecules. The best performing models were subsequently tested on an external test set of newly designed and synthesized analogs. In vitro testing showed a good correlation between the predicted and experimentally observed IC₅₀ values. Thus, the generated models can be considered as interesting tools for the identification of novel smHDAC8 inhibitors. Full article

(This article belongs to the Special Issue Computational Methods for Drug Discovery and Design II)

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17 pages, 3766 KiB

Open AccessArticle

Identification of Flavonoids as Putative ROS-1 Kinase Inhibitors Using Pharmacophore Modeling for NSCLC Therapeutics

by Shraddha Parate, Vikas Kumar, Jong Chan Hong and Keun Woo Lee

Molecules 2021, 26(8), 2114; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26082114 - 07 Apr 2021

Cited by 7 | Viewed by 2695

Abstract

Non-small cell lung cancer (NSCLC) is a lethal non-immunogenic malignancy and proto-oncogene ROS-1 tyrosine kinase is one of its clinically relevant oncogenic markers. The ROS-1 inhibitor, crizotinib, demonstrated resistance due to the Gly2032Arg mutation. To curtail this resistance, researchers developed lorlatinib against the mutated kinase. In the present study, a receptor-ligand pharmacophore model exploiting the key features of lorlatinib binding with ROS-1 was exploited to identify inhibitors against the wild-type (WT) and the mutant (MT) kinase domain. The developed model was utilized to virtually screen the TimTec flavonoids database and the retrieved drug-like hits were subjected for docking with the WT and MT ROS-1 kinase. A total of 10 flavonoids displayed higher docking scores than lorlatinib. Subsequent molecular dynamics simulations of the acquired flavonoids with WT and MT ROS-1 revealed no steric clashes with the Arg2032 (MT ROS-1). The binding free energy calculations computed via molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) demonstrated one flavonoid (Hit) with better energy than lorlatinib in binding with WT and MT ROS-1. The Hit compound was observed to bind in the ROS-1 selectivity pocket comprised of residues from the β-3 sheet and DFG-motif. The identified Hit from this investigation could act as a potent WT and MT ROS-1 inhibitor. Full article

(This article belongs to the Special Issue Computational Methods for Drug Discovery and Design II)

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Graphical abstract

19 pages, 5199 KiB

Open AccessArticle

Computational Modeling to Explain Why 5,5-Diarylpentadienamides are TRPV1 Antagonists

by Julio Caballero

Molecules 2021, 26(6), 1765; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26061765 - 21 Mar 2021

Cited by 6 | Viewed by 2204

Abstract

Several years ago, the crystallographic structures of the transient receptor potential vanilloid 1 (TRPV1) in the presence of agonists and antagonists were reported, providing structural information about its chemical activation and inactivation. TRPV1’s activation increases the transport of calcium and sodium ions, leading to the excitation of sensory neurons and the perception of pain. On the other hand, its antagonistic inactivation has been explored to design analgesic drugs. The interactions between the antagonists 5,5-diarylpentadienamides (DPDAs) and TRPV1 were studied here to explain why they inactivate TRPV1. The present work identified the structural features of TRPV1–DPDA complexes, starting with a consideration of the orientations of the ligands inside the TRPV1 binding site by using molecular docking. After this, a chemometrics analysis was performed (i) to compare the orientations of the antagonists (by using LigRMSD), (ii) to describe the recurrent interactions between the protein residues and ligand groups in the complexes (by using interaction fingerprints), and (iii) to describe the relationship between topological features of the ligands and their differential antagonistic activities (by using a quantitative structure–activity relationship (QSAR) with 2D autocorrelation descriptors). The interactions between the DPDA groups and the residues Y511, S512, T550, R557, and E570 (with a recognized role in the binding of classic ligands), and the occupancy of isoquinoline or 3-hydroxy-3,4-dihydroquinolin-2(1H)-one groups of the DPDAs in the vanilloid pocket of TRPV1 were clearly described. Based on the results, the structural features that explain why DPDAs inactivate TRPV1 were clearly exposed. These features can be considered for the design of novel TRPV1 antagonists. Full article

(This article belongs to the Special Issue Computational Methods for Drug Discovery and Design II)

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