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Special Issue "In-Silico Drug Design and In-Silico Screening"

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

Deadline for manuscript submissions: closed (31 March 2014)

Special Issue Editors

Guest Editor
Prof. Dr. Iwao Ojima

Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York, USA
Website | E-Mail
Interests: drug discovery; anticancer agents; antimicrobial agents; anti-inflammatory agents; enzyme inhibitors; computer-aided drug design; structure-based drug design
Guest Editor
Prof. Dr. Robert C. Rizzo

Department of Applied Mathematics and Statistics, Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794, USA
Website | E-Mail
Interests: structure-based drug design; docking; virtual screening; molecular dynamics; infectious disease

Special Issue Information

Dear Colleagues,

Computer modeling’s overall usefulness in the drug discovery process is well established. Such modeling at the atomic level is an integral part of the paradigm of "structure-based design." Computational approaches, such as docking, can be used to predict how a small molecule ligand binds to a target. Given the recent advances in large-scale computing, large ligand libraries on the order of several millions of compounds can be effectively screened in silico to identify promising drug leads (virtual screening) for experimental testing. The screening of smaller molecular fragments using computers is another powerful approach. This screening can be used to identify binding site "hotpots" for which specific regions can be targeted with specific functional groups that have good steric and energetic complementarity. Other computational methods, such as de novo design, provide unique leverage for the informed design of new ligands "from scratch", as well as refinement of current leads prior to organic synthesis.  Importantly, an active area of research for many research groups is continued improvement of the algorithms controlling the sampling and scoring of the inter- and intra molecular degrees of freedom that define a ligand binding geometry (pose). In this Special Issue of Molecules entitled "In-Silico Drug Design and In-Silico Screening", we invite manuscript submissions that discuss both the development and the application of computational methods. Original research articles or reviews that combine computational predications with experimental testing and verification are especially welcome.

Dr. Robert C. Rizzo
Dr. Iwao Ojima
Guest Editors

Submission

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a 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 monthly journal published by MDPI.

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Keywords

  • structure-based drug design
  • computer-aided drug design
  • in silico drug design
  • virtual screening
  • in silico screening
  • docking
  • lead discovery
  • binding pose identification
  • database enrichment
  • drug discovery

Published Papers (13 papers)

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Research

Jump to: Review

Open AccessArticle Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors
Molecules 2015, 20(1), 1014-1030; doi:10.3390/molecules20011014
Received: 11 September 2014 / Accepted: 29 November 2014 / Published: 9 January 2015
Cited by 4 | PDF Full-text (2411 KB) | HTML Full-text | XML Full-text
Abstract
The mitochondrial cytochrome P450 enzymes inhibitor steroid 11β-hydroxylase (CYP11B1) can decrease the production of cortisol. Therefore, these inhibitors have an effect in the treatment of Cushing’s syndrome. A pharmacophore model generated by Genetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets (GALAHAD)
[...] Read more.
The mitochondrial cytochrome P450 enzymes inhibitor steroid 11β-hydroxylase (CYP11B1) can decrease the production of cortisol. Therefore, these inhibitors have an effect in the treatment of Cushing’s syndrome. A pharmacophore model generated by Genetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets (GALAHAD) was used to align the compounds and perform comparative molecular field analysis (CoMFA) with Q2 = 0.658, R2 = 0.959. The pharmacophore model contained six hydrophobic regions and one acceptor atom, and electropositive and bulky substituents would be tolerated at the A and B sites, respectively. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study based on the alignment with the atom root mean square (RMS) was applied using comparative molecular field analysis (CoMFA) with Q2 = 0.666, R2 = 0.978, and comparative molecular similarity indices analysis (CoMSIA) with Q2 = 0.721, R2 = 0.972. These results proved that all the models have good predictability of the bioactivities of inhibitors. Furthermore, the QSAR models indicated that a hydrogen bond acceptor substituent would be disfavored at the A and B groups, while hydrophobic groups would be favored at the B site. The three-dimensional (3D) model of the CYP11B1 was generated based on the crystal structure of the CYP11B2 (PDB code 4DVQ). In order to probe the ligand-binding modes, Surflex-dock was employed to dock CYP11B1 inhibitory compounds into the active site of the receptor. The docking result showed that the imidazolidine ring of CYP11B1 inhibitors form H bonds with the amino group of residue Arg155 and Arg519, which suggested that an electronegative substituent at these positions could enhance the activities of compounds. All the models generated by GALAHAD QSAR and Docking methods provide guidance about how to design novel and potential drugs for Cushing’s syndrome treatment. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
Open AccessArticle Playing with Opening and Closing of Heterocycles: Using the Cusmano-Ruccia Reaction to Develop a Novel Class of Oxadiazolothiazinones, Active as Calcium Channel Modulators and P-Glycoprotein Inhibitors
Molecules 2014, 19(10), 16543-16572; doi:10.3390/molecules191016543
Received: 20 June 2014 / Revised: 15 August 2014 / Accepted: 4 September 2014 / Published: 14 October 2014
Cited by 2 | PDF Full-text (4448 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
As a result of the ring-into-ring conversion of nitrosoimidazole derivatives, we obtained a molecular scaffold that, when properly decorated, is able to decrease inotropy by blocking L-type calcium channels. Previously, we used this scaffold to develop a quantitative structure-activity relationship (QSAR) model, and
[...] Read more.
As a result of the ring-into-ring conversion of nitrosoimidazole derivatives, we obtained a molecular scaffold that, when properly decorated, is able to decrease inotropy by blocking L-type calcium channels. Previously, we used this scaffold to develop a quantitative structure-activity relationship (QSAR) model, and we used the most potent oxadiazolothiazinone as a template for ligand-based virtual screening. Here, we enlarge the diversity of chemical decorations, present the synthesis and in vitro data for 11 new derivatives, and develop a new 3D-QSAR model with recent in silico techniques. We observed a key role played by the oxadiazolone moiety: given the presence of positively charged calcium ions in the transmembrane channel protein, we hypothesize the formation of a ternary complex between the oxadiazolothiazinone, the Ca2+ ion and the protein. We have supported this hypothesis by means of pharmacophore generation and through the docking of the pharmacophore into a homology model of the protein. We also studied with docking experiments the interaction with a homology model of P-glycoprotein, which is inhibited by this series of molecules, and provided further evidence toward the relevance of this scaffold in biological interactions. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Open AccessArticle Investigation of the Flexibility of Protein Kinases Implicated in the Pathology of Alzheimer’s Disease
Molecules 2014, 19(7), 9134-9159; doi:10.3390/molecules19079134
Received: 4 May 2014 / Revised: 16 June 2014 / Accepted: 19 June 2014 / Published: 30 June 2014
Cited by 2 | PDF Full-text (7383 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The pathological characteristics of Alzheimer’s Disease (AD) have been linked to the activity of three particular kinases—Glycogen Synthase Kinase 3β (GSK3β), Cyclin-Dependent Kinase 5 (CDK5) and Extracellular-signal Regulated Kinase 2 (ERK2). As a consequence, the design of selective, potent and drug-like inhibitors of
[...] Read more.
The pathological characteristics of Alzheimer’s Disease (AD) have been linked to the activity of three particular kinases—Glycogen Synthase Kinase 3β (GSK3β), Cyclin-Dependent Kinase 5 (CDK5) and Extracellular-signal Regulated Kinase 2 (ERK2). As a consequence, the design of selective, potent and drug-like inhibitors of these kinases is of particular interest. Structure-based design methods are well-established in the development of kinase inhibitors. However, progress in this field is limited by the difficulty in obtaining X-ray crystal structures suitable for drug design and by the inability of this method to resolve highly flexible regions of the protein that are crucial for ligand binding. To address this issue, we have undertaken a study of human protein kinases CDK5/p25, CDK5, ERK2 and GSK3β using both conventional molecular dynamics (MD) and the new Active Site Pressurisation (ASP) methodology, to look for kinase-specific patterns of flexibility that could be leveraged for the design of selective inhibitors. ASP was used to examine the intrinsic flexibility of the ATP-binding pocket for CDK5/p25, CDK5 and GSK3β where it is shown to be capable of inducing significant conformational changes when compared with X-ray crystal structures. The results from these experiments were used to quantify the dynamics of each protein, which supported the observations made from the conventional MD simulations. Additional information was also derived from the ASP simulations, including the shape of the ATP-binding site and the rigidity of the ATP-binding pocket. These observations may be exploited in the design of selective inhibitors of GSK3β, CDK5 and ERK2. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Open AccessArticle Drug-Induced Conformational Population Shifts in Topoisomerase-DNA Ternary Complexes
Molecules 2014, 19(6), 7415-7428; doi:10.3390/molecules19067415
Received: 7 March 2014 / Revised: 26 May 2014 / Accepted: 29 May 2014 / Published: 5 June 2014
Cited by 4 | PDF Full-text (2044 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Type II topoisomerases (TOP2) are enzymes that resolve the topological problems during DNA replication and transcription by transiently cleaving both strands and forming a cleavage complex with the DNA. Several prominent anti-cancer agents inhibit TOP2 by stabilizing the cleavage complex and engendering permanent
[...] Read more.
Type II topoisomerases (TOP2) are enzymes that resolve the topological problems during DNA replication and transcription by transiently cleaving both strands and forming a cleavage complex with the DNA. Several prominent anti-cancer agents inhibit TOP2 by stabilizing the cleavage complex and engendering permanent DNA breakage. To discriminate drug binding modes in TOP2-α and TOP2-β, we applied our newly developed scoring function, dubbed AutoDock4RAP, to evaluate the binding modes of VP-16, m-AMSA, and mitoxantrone to the cleavage complexes. Docking reproduced crystallographic binding mode of VP-16 in a ternary complex of TOP2-β with root-mean-square deviation of 0.65 Å. Molecular dynamics simulation of the complex confirmed the crystallographic binding mode of VP-16 and the conformation of the residue R503. Drug-related conformational changes in R503 have been observed in ternary complexes with m-AMSA and mitoxantrone. However, the R503 rotamers in these two simulations deviate from their crystallographic conformations, indicating a relaxation dynamics from the conformations determined with the drug replacement procedure. The binding mode of VP-16 in the cleavage complex of TOP2-α was determined by the conjoint use of docking and molecular dynamics simulations, which fell within a similar binding pocket of TOP2-β cleavage complex. Our findings may facilitate more efficient design efforts targeting TOP2-α specific drugs. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Open AccessArticle Combination of 2D/3D Ligand-Based Similarity Search in Rapid Virtual Screening from Multimillion Compound Repositories. Selection and Biological Evaluation of Potential PDE4 and PDE5 Inhibitors
Molecules 2014, 19(6), 7008-7039; doi:10.3390/molecules19067008
Received: 25 March 2014 / Revised: 21 May 2014 / Accepted: 22 May 2014 / Published: 28 May 2014
Cited by 4 | PDF Full-text (1888 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost effective approach. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compound databases but the generated library requires further focusing
[...] Read more.
Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost effective approach. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compound databases but the generated library requires further focusing by various 2D/3D chemoinformatics tools. We report here a combination of the 2D approach with a ligand-based 3D method (Screen3D) which applies flexible matching to align reference and target compounds in a dynamic manner and thus to assess their structural and conformational similarity. In the first case study we compared the 2D and 3D similarity scores on an existing dataset derived from the biological evaluation of a PDE5 focused library. Based on the obtained similarity metrices a fusion score was proposed. The fusion score was applied to refine the 2D similarity search in a second case study where we aimed at selecting and evaluating a PDE4B focused library. The application of this fused 2D/3D similarity measure led to an increase of the hit rate from 8.5% (1st round, 47% inhibition at 10 µM) to 28.5% (2nd round at 50% inhibition at 10 µM) and the best two hits had 53 nM inhibitory activities. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Open AccessArticle In Silico Docking, Molecular Dynamics and Binding Energy Insights into the Bolinaquinone-Clathrin Terminal Domain Binding Site
Molecules 2014, 19(5), 6609-6622; doi:10.3390/molecules19056609
Received: 20 March 2014 / Revised: 6 May 2014 / Accepted: 14 May 2014 / Published: 22 May 2014
Cited by 3 | PDF Full-text (3854 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Clathrin-mediated endocytosis (CME) is a process that regulates selective internalization of important cellular cargo using clathrin-coated vesicles. Perturbation of this process has been linked to many diseases including cancer and neurodegenerative conditions. Chemical proteomics identified the marine metabolite, 2-hydroxy-5-methoxy-3-(((1S,4aS,8a
[...] Read more.
Clathrin-mediated endocytosis (CME) is a process that regulates selective internalization of important cellular cargo using clathrin-coated vesicles. Perturbation of this process has been linked to many diseases including cancer and neurodegenerative conditions. Chemical proteomics identified the marine metabolite, 2-hydroxy-5-methoxy-3-(((1S,4aS,8aS)-1,4a,5-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-2-yl)methyl)cyclohexa- 2,5-diene-1,4-dione (bolinaquinone) as a clathrin inhibitor. While being an attractive medicinal chemistry target, the lack of data about bolinaquinone’s mode of binding to the clathrin enzyme represents a major limitation for its structural optimization. We have used a molecular modeling approach to rationalize the observed activity of bolinaquinone and to predict its mode of binding with the clathrin terminal domain (CTD). The applied protocol started by global rigid-protein docking followed by flexible docking, molecular dynamics and linear interaction energy calculations. The results revealed the potential of bolinaquinone to interact with various pockets within the CTD, including the clathrin-box binding site. The results also highlight the importance of electrostatic contacts over van der Waals interactions for proper binding between bolinaquinone and its possible binding sites. This study provides a novel model that has the potential to allow rapid elaboration of bolinaquinone analogues as a new class of clathrin inhibitors. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Open AccessArticle Integrated Computational Tools for Identification of CCR5 Antagonists as Potential HIV-1 Entry Inhibitors: Homology Modeling, Virtual Screening, Molecular Dynamics Simulations and 3D QSAR Analysis
Molecules 2014, 19(4), 5243-5265; doi:10.3390/molecules19045243
Received: 27 January 2014 / Revised: 1 April 2014 / Accepted: 9 April 2014 / Published: 23 April 2014
Cited by 7 | PDF Full-text (2801 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Using integrated in-silico computational techniques, including homology modeling, structure-based and pharmacophore-based virtual screening, molecular dynamic simulations, per-residue energy decomposition analysis and atom-based 3D-QSAR analysis, we proposed ten novel compounds as potential CCR5-dependent HIV-1 entry inhibitors. Via validated docking calculations, binding free energies revealed
[...] Read more.
Using integrated in-silico computational techniques, including homology modeling, structure-based and pharmacophore-based virtual screening, molecular dynamic simulations, per-residue energy decomposition analysis and atom-based 3D-QSAR analysis, we proposed ten novel compounds as potential CCR5-dependent HIV-1 entry inhibitors. Via validated docking calculations, binding free energies revealed that novel leads demonstrated better binding affinities with CCR5 compared to maraviroc, an FDA-approved HIV-1 entry inhibitor and in clinical use. Per-residue interaction energy decomposition analysis on the averaged MD structure showed that hydrophobic active residues Trp86, Tyr89 and Tyr108 contributed the most to inhibitor binding. The validated 3D-QSAR model showed a high cross-validated rcv2 value of 0.84 using three principal components and non-cross-validated r2 value of 0.941. It was also revealed that almost all compounds in the test set and training set yielded a good predicted value. Information gained from this study could shed light on the activity of a new series of lead compounds as potential HIV entry inhibitors and serve as a powerful tool in the drug design and development machinery. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
Open AccessArticle Inhibition and Biochemical Characterization of Methicillin-Resistant Staphylococcus aureus Shikimate Dehydrogenase: An in Silico and Kinetic Study
Molecules 2014, 19(4), 4491-4509; doi:10.3390/molecules19044491
Received: 6 February 2014 / Revised: 3 April 2014 / Accepted: 4 April 2014 / Published: 10 April 2014
Cited by 2 | PDF Full-text (2040 KB) | HTML Full-text | XML Full-text
Abstract
Methicillin-resistant Staphylococcus auerus (MRSA) strains are having a major impact worldwide, and due to their resistance to all β-lactams, an urgent need for new drugs is emerging. In this regard, the shikimate pathway is considered to be one of the metabolic features of
[...] Read more.
Methicillin-resistant Staphylococcus auerus (MRSA) strains are having a major impact worldwide, and due to their resistance to all β-lactams, an urgent need for new drugs is emerging. In this regard, the shikimate pathway is considered to be one of the metabolic features of bacteria and is absent in humans. Therefore enzymes involved in this route, such as shikimate dehydrogenase (SDH), are considered excellent targets for discovery of novel antibacterial drugs. In this study, the SDH from MRSA (SaSDH) was characterized. The results showed that the enzyme is a monomer with a molecular weight of 29 kDa, an optimum temperature of 65 °C, and a maximal pH range of 9–11 for its activity. Kinetic studies revealed that SDH showed Michaelis-Menten kinetics toward both substrates (shikimate and NADP+). Initial velocity analysis suggested that SaSDH catalysis followed a sequential random mechanism. Additionally, a tridimensional model of SaSDH was obtained by homology modeling and validated. Through virtual screening three inhibitors of SaSDH were found (compounds 238, 766 and 894) and their inhibition constants and mechanism were obtained. Flexible docking studies revealed that these molecules make interactions with catalytic residues. The data of this study could serve as starting point in the search of new chemotherapeutic agents against MRSA. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Open AccessArticle Computational Redesign of Bacterial Biotin Carboxylase Inhibitors Using Structure-Based Virtual Screening of Combinatorial Libraries
Molecules 2014, 19(4), 4021-4045; doi:10.3390/molecules19044021
Received: 21 February 2014 / Revised: 19 March 2014 / Accepted: 25 March 2014 / Published: 2 April 2014
Cited by 5 | PDF Full-text (4483 KB) | HTML Full-text | XML Full-text
Abstract
As the spread of antibiotic resistant bacteria steadily increases, there is an urgent need for new antibacterial agents. Because fatty acid synthesis is only used for membrane biogenesis in bacteria, the enzymes in this pathway are attractive targets for antibacterial agent development. Acetyl-CoA
[...] Read more.
As the spread of antibiotic resistant bacteria steadily increases, there is an urgent need for new antibacterial agents. Because fatty acid synthesis is only used for membrane biogenesis in bacteria, the enzymes in this pathway are attractive targets for antibacterial agent development. Acetyl-CoA carboxylase catalyzes the committed and regulated step in fatty acid synthesis. In bacteria, the enzyme is composed of three distinct protein components: biotin carboxylase, biotin carboxyl carrier protein, and carboxyltransferase. Fragment-based screening revealed that amino-oxazole inhibits biotin carboxylase activity and also exhibits antibacterial activity against Gram-negative organisms. In this report, we redesigned previously identified lead inhibitors to expand the spectrum of bacteria sensitive to the amino-oxazole derivatives by including Gram-positive species. Using 9,411 small organic building blocks, we constructed a diverse combinatorial library of 1.2 × 108 amino-oxazole derivatives. A subset of 9 × 106 of these compounds were subjected to structure-based virtual screening against seven biotin carboxylase isoforms using similarity-based docking by eSimDock. Potentially broad-spectrum antibiotic candidates were selected based on the consensus ranking by several scoring functions including non-linear statistical models implemented in eSimDock and traditional molecular mechanics force fields. The analysis of binding poses of the top-ranked compounds docked to biotin carboxylase isoforms suggests that: (1) binding of the amino-oxazole anchor is stabilized by a network of hydrogen bonds to residues 201, 202 and 204; (2) halogenated aromatic moieties attached to the amino-oxazole scaffold enhance interactions with a hydrophobic pocket formed by residues 157, 169, 171 and 203; and (3) larger substituents reach deeper into the binding pocket to form additional hydrogen bonds with the side chains of residues 209 and 233. These structural insights into drug-biotin carboxylase interactions will be tested experimentally in in vitro and in vivo systems to increase the potency of amino-oxazole inhibitors towards both Gram-negative as well as Gram-positive species. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
Open AccessArticle Theoretical Study on the Allosteric Regulation of an Oligomeric Protease from Pyrococcus horikoshii by Cl Ion
Molecules 2014, 19(2), 1828-1842; doi:10.3390/molecules19021828
Received: 19 December 2013 / Revised: 23 January 2014 / Accepted: 27 January 2014 / Published: 7 February 2014
Cited by 1 | PDF Full-text (2217 KB) | HTML Full-text | XML Full-text
Abstract
The thermophilic intracellular protease (PH1704) from Pyrococcus horikoshii that functions as an oligomer (hexamer or higher forms) has proteolytic activity and remarkable stability. PH1704 is classified as a member of the C56 family of peptidases. This study is the first to observe that
[...] Read more.
The thermophilic intracellular protease (PH1704) from Pyrococcus horikoshii that functions as an oligomer (hexamer or higher forms) has proteolytic activity and remarkable stability. PH1704 is classified as a member of the C56 family of peptidases. This study is the first to observe that the use of Cl as an allosteric inhibitor causes appreciable changes in the catalytic activity of the protease. Theoretical methods were used for further study. Quantum mechanical calculations indicated the binding mode of Cl with Arg113. A molecular dynamics simulation explained how Cl stabilized distinct contact species and how it controls the enzyme activity. The new structural insights obtained from this study are expected to stimulate further biochemical studies on the structures and mechanisms of allosteric proteases. It is clear that the discovery of new allosteric sites of the C56 family of peptidases may generate opportunities for pharmaceutical development and increases our understanding of the basic biological processes of this peptidase family. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Open AccessArticle In Vitro Evaluation of Novel Inhibitors against the NS2B-NS3 Protease of Dengue Fever Virus Type 4
Molecules 2013, 18(12), 15600-15612; doi:10.3390/molecules181215600
Received: 28 October 2013 / Revised: 2 December 2013 / Accepted: 11 December 2013 / Published: 13 December 2013
Cited by 8 | PDF Full-text (897 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3pro) of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual
[...] Read more.
The discovery of potent therapeutic compounds against dengue virus is urgently needed. The NS2B-NS3 protease (NS2B-NS3pro) of dengue fever virus carries out all enzymatic activities needed for polyprotein processing and is considered to be amenable to antiviral inhibition by analogy. Virtual screening of 300,000 compounds using Autodock 3 on the GVSS platform was conducted to identify novel inhibitors against the NS2B-NS3pro. Thirty-six compounds were selected for in vitro assay against NS2B-NS3pro expressed in Pichia pastoris. Seven novel compounds were identified as inhibitors with IC50 values of 3.9 ± 0.6–86.7 ± 3.6 μM. Three strong NS2B-NS3pro inhibitors were further confirmed as competitive inhibitors with Ki values of 4.0 ± 0.4, 4.9 ± 0.3, and 3.4 ± 0.1 μM, respectively. Hydrophobic and hydrogen bond interactions between amino acid residues in the NS3pro active site with inhibition compounds were also identified. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
Open AccessArticle The Effect of Conformational Variability of Phosphotriesterase upon N-acyl-L-homoserine Lactone and Paraoxon Binding: Insights from Molecular Dynamics Studies
Molecules 2013, 18(12), 15501-15518; doi:10.3390/molecules181215501
Received: 6 November 2013 / Revised: 3 December 2013 / Accepted: 6 December 2013 / Published: 12 December 2013
Cited by 3 | PDF Full-text (3026 KB) | HTML Full-text | XML Full-text
Abstract
The organophosphorous hydrolase (PTE) from Brevundimonas diminuta is capable of degrading extremely toxic organophosphorous compounds with a high catalytic turnover and broad substrate specificity. Although the natural substrate for PTE is unknown, its loop remodeling (loop 7-2/H254R) led to the emergence of a
[...] Read more.
The organophosphorous hydrolase (PTE) from Brevundimonas diminuta is capable of degrading extremely toxic organophosphorous compounds with a high catalytic turnover and broad substrate specificity. Although the natural substrate for PTE is unknown, its loop remodeling (loop 7-2/H254R) led to the emergence of a homoserine lactonase (HSL) activity that is undetectable in PTE (kcat/km values of up to 2 × 104), with only a minor decrease in PTE paraoxonase activity. In this study, homology modeling and molecular dynamics simulations have been undertaken seeking to explain the reason for the substrate specificity for the wild-type and the loop 7-2/H254R variant. The cavity volume estimated results showed that the active pocket of the variant was almost two fold larger than that of the wild-type (WT) enzyme. pKa calculations for the enzyme (the WT and the variant) showed a significant pKa shift from WT standard values (ΔpKa = 3.5 units) for the His254residue (in the Arg254 variant). Molecular dynamics simulations indicated that the displacement of loops 6 and 7 over the active site in loop 7-2/H254R variant is useful for N-acyl-L-homoserine lactone (C4-HSL) with a large aliphatic chain to site in the channels easily. Thence the expanding of the active pocket is beneficial to C4-HSL binding and has a little effect on paraoxon binding. Our results provide a new theoretical contribution of loop remodeling to the rapid divergence of new enzyme functions. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Review

Jump to: Research

Open AccessReview Challenges, Applications, and Recent Advances of Protein-Ligand Docking in Structure-Based Drug Design
Molecules 2014, 19(7), 10150-10176; doi:10.3390/molecules190710150
Received: 23 April 2014 / Revised: 13 June 2014 / Accepted: 2 July 2014 / Published: 11 July 2014
Cited by 21 | PDF Full-text (238 KB) | HTML Full-text | XML Full-text
Abstract
The docking methods used in structure-based virtual database screening offer the ability to quickly and cheaply estimate the affinity and binding mode of a ligand for the protein receptor of interest, such as a drug target. These methods can be used to enrich
[...] Read more.
The docking methods used in structure-based virtual database screening offer the ability to quickly and cheaply estimate the affinity and binding mode of a ligand for the protein receptor of interest, such as a drug target. These methods can be used to enrich a database of compounds, so that more compounds that are subsequently experimentally tested are found to be pharmaceutically interesting. In addition, like all virtual screening methods used for drug design, structure-based virtual screening can focus on curated libraries of synthesizable compounds, helping to reduce the expense of subsequent experimental verification. In this review, we introduce the protein-ligand docking methods used for structure-based drug design and other biological applications. We discuss the fundamental challenges facing these methods and some of the current methodological topics of interest. We also discuss the main approaches for applying protein-ligand docking methods. We end with a discussion of the challenging aspects of evaluating or benchmarking the accuracy of docking methods for their improvement, and discuss future directions. Full article
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)

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