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Molecular Docking in Drug Design

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

Deadline for manuscript submissions: closed (31 March 2015) | Viewed by 215787

Special Issue Editor

Special Issue Information

Dear Colleagues,

Molecular docking is an invaluable tool in modern drug discovery and design. In this special issue, a number of articles in the field of molecular docking applied to the drug design world will be published. Although many algorithms have been disclosed and new docking programs are constantly released, there is still much to do. The great difficulty in any docking program is the ability to recognize the right pose among the generated conformations. To face this problem, many authors have proposed different approaches like consensus scoring, consensus docking and external independent scoring, but no one has yes reached a good level to definitively assess the docking of a given small molecule into the desired target.

Therefore, there is still the need to improve molecular docking and the main goal of this special issue is to report the newest approaches in molecular docking application to drug design.

Prof. Dr. Rino Ragno
Guest Editor

Manuscript Submission Information

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Keywords

  • molecular docking
  • molecular recognition
  • structure based drug design
  • scoring function
  • cross docking
  • ensemble docking
  • flexible docking
  • binding mode
  • docking assessment

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Published Papers (15 papers)

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Research

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3299 KiB  
Article
Identification of Hydrophobic Interfaces in Protein-Ligand Complexes by Selective Saturation Transfer NMR Spectroscopy
by Fabien Ferrage, Kaushik Dutta and David Cowburn
Molecules 2015, 20(12), 21992-21999; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules201219824 - 09 Dec 2015
Cited by 3 | Viewed by 5454
Abstract
The proper characterization of protein-ligand interfaces is essential for structural biology, with implications ranging from the fundamental understanding of biological processes to pharmacology. Nuclear magnetic resonance is a powerful technique for such studies. We propose a novel approach to the direct determination of [...] Read more.
The proper characterization of protein-ligand interfaces is essential for structural biology, with implications ranging from the fundamental understanding of biological processes to pharmacology. Nuclear magnetic resonance is a powerful technique for such studies. We propose a novel approach to the direct determination of the likely pose of a peptide ligand onto a protein partner, by using frequency-selective cross-saturation with a low stringency isotopic labeling methods. Our method illustrates a complex of the Src homology 3 domain of C-terminal Src kinase with a peptide from the proline-enriched tyrosine phosphatase. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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4535 KiB  
Article
Molecular Docking and Multivariate Analysis of Xanthones as Antimicrobial and Antiviral Agents
by Freddy A. Bernal and Ericsson Coy-Barrera
Molecules 2015, 20(7), 13165-13204; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules200713165 - 21 Jul 2015
Cited by 12 | Viewed by 8780
Abstract
Xanthones are secondary metabolites which have drawn considerable interest over the last decades due to their antimicrobial properties, among others. A great number of this kind of compounds has been therefore reported, but there is a limited amount of studies on screening for [...] Read more.
Xanthones are secondary metabolites which have drawn considerable interest over the last decades due to their antimicrobial properties, among others. A great number of this kind of compounds has been therefore reported, but there is a limited amount of studies on screening for biological activity. Thus, as part of our research on antimicrobial agents of natural origin, a set of 272 xanthones were submitted to molecular docking (MD) calculations with a group of seven fungal and two viral enzymes. The results indicated that prenylated xanthones are important hits for inhibition of the analyzed enzymes. The MD scores were also analyzed by multivariate statistics. Important structural details were found to be crucial for the inhibition of the tested enzymes by the xanthones. In addition, the classification of active xanthones can be achieved by statistical analysis on molecular docking scores by an affinity-antifungal activity relationship approach. The obtained results therefore are a suitable starting point for the development of antifungal and antiviral agents based on xanthones. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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6164 KiB  
Article
Coarse-Grained Modeling of Peptide Docking Associated with Large Conformation Transitions of the Binding Protein: Troponin I Fragment–Troponin C System
by Jacek Wabik, Mateusz Kurcinski and Andrzej Kolinski
Molecules 2015, 20(6), 10763-10780; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules200610763 - 11 Jun 2015
Cited by 9 | Viewed by 8248
Abstract
Most of the current docking procedures are focused on fine conformational adjustments of assembled complexes and fail to reproduce large-scale protein motion. In this paper, we test a new modeling approach developed to address this problem. CABS-dock is a versatile and efficient tool [...] Read more.
Most of the current docking procedures are focused on fine conformational adjustments of assembled complexes and fail to reproduce large-scale protein motion. In this paper, we test a new modeling approach developed to address this problem. CABS-dock is a versatile and efficient tool for modeling the structure, dynamics and interactions of protein complexes. The docking protocol employs a coarse-grained representation of proteins, a simplified model of interactions and advanced protocols for conformational sampling. CABS-dock is one of the very few tools that allow unrestrained docking with large conformational freedom of the receptor. In an example application we modeled the process of complex assembly between two proteins: Troponin C (TnC) and the N-terminal helix of Troponin I (TnI N-helix), which occurs in vivo during muscle contraction. Docking simulations illustrated how the TnC molecule undergoes significant conformational transition on complex formation, a phenomenon that can be modeled only when protein flexibility is properly accounted for. This way our procedure opens up a new possibility for studying mechanisms of protein complex assembly, which may be a supporting tool for rational drug design. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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2684 KiB  
Article
Computational Studies of Benzoxazinone Derivatives as Antiviral Agents against Herpes Virus Type 1 Protease
by Juliana F. R. Mello, Nathália C. Botelho, Alessandra M. T. Souza, Riethe Oliveira, Monique A. Brito, Bárbara De A. Abrahim-Vieira, Ana Carolina R. Sodero, Helena C. Castro, Lucio M. Cabral, Leonardo A. Miceli and Carlos R. Rodrigues
Molecules 2015, 20(6), 10689-10704; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules200610689 - 10 Jun 2015
Cited by 7 | Viewed by 7769
Abstract
Herpes simplex virus infections have been described in the medical literature for centuries, yet the the drugs available nowadays for therapy are largely ineffective and low oral bioavailability plays an important role on the inefficacy of the treatments. Additionally, the details of the [...] Read more.
Herpes simplex virus infections have been described in the medical literature for centuries, yet the the drugs available nowadays for therapy are largely ineffective and low oral bioavailability plays an important role on the inefficacy of the treatments. Additionally, the details of the inhibition of Herpes Virus type 1 are still not fully understood. Studies have shown that several viruses encode one or more proteases required for the production new infectious virions. This study presents an analysis of the interactions between HSV-1 protease and benzoxazinone derivatives through a combination of structure-activity relationships, comparative modeling and molecular docking studies. The structure activity relationship results showed an important contribution of hydrophobic and polarizable groups and limitations for bulky groups in specific positions. Two Herpes Virus type 1 protease models were constructed and compared to achieve the best model which was obtained by MODELLER. Molecular docking results pointed to an important interaction between the most potent benzoxazinone derivative and Ser129, consistent with previous mechanistic data. Moreover, we also observed hydrophobic interactions that may play an important role in the stabilization of inhibitors in the active site. Finally, we performed druglikeness and drugscore studies of the most potent derivatives and the drugs currently used against Herpes virus. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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3354 KiB  
Article
Solving Molecular Docking Problems with Multi-Objective Metaheuristics
by María Jesús García-Godoy, Esteban López-Camacho, José García-Nieto, Antonio J. Nebro and José F. Aldana-Montes
Molecules 2015, 20(6), 10154-10183; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules200610154 - 02 Jun 2015
Cited by 22 | Viewed by 8633
Abstract
Molecular docking is a hard optimization problem that has been tackled in the past with metaheuristics, demonstrating new and challenging results when looking for one objective: the minimum binding energy. However, only a few papers can be found in the literature that deal [...] Read more.
Molecular docking is a hard optimization problem that has been tackled in the past with metaheuristics, demonstrating new and challenging results when looking for one objective: the minimum binding energy. However, only a few papers can be found in the literature that deal with this problem by means of a multi-objective approach, and no experimental comparisons have been made in order to clarify which of them has the best overall performance. In this paper, we use and compare, for the first time, a set of representative multi-objective optimization algorithms applied to solve complex molecular docking problems. The approach followed is focused on optimizing the intermolecular and intramolecular energies as two main objectives to minimize. Specifically, these algorithms are: two variants of the non-dominated sorting genetic algorithm II (NSGA-II), speed modulation multi-objective particle swarm optimization (SMPSO), third evolution step of generalized differential evolution (GDE3), multi-objective evolutionary algorithm based on decomposition (MOEA/D) and S-metric evolutionary multi-objective optimization (SMS-EMOA). We assess the performance of the algorithms by applying quality indicators intended to measure convergence and the diversity of the generated Pareto front approximations. We carry out a comparison with another reference mono-objective algorithm in the problem domain (Lamarckian genetic algorithm (LGA) provided by the AutoDock tool). Furthermore, the ligand binding site and molecular interactions of computed solutions are analyzed, showing promising results for the multi-objective approaches. In addition, a case study of application for aeroplysinin-1 is performed, showing the effectiveness of our multi-objective approach in drug discovery. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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1203 KiB  
Article
DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations
by Alberto Cuzzolin, Mattia Sturlese, Ivana Malvacio, Antonella Ciancetta and Stefano Moro
Molecules 2015, 20(6), 9977-9993; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules20069977 - 29 May 2015
Cited by 38 | Viewed by 11290
Abstract
Virtual screening (VS) is a computational methodology that streamlines the drug discovery process by reducing costs and required resources through the in silico identification of potential drug candidates. Structure-based VS (SBVS) exploits knowledge about the three-dimensional (3D) structure of protein targets and uses [...] Read more.
Virtual screening (VS) is a computational methodology that streamlines the drug discovery process by reducing costs and required resources through the in silico identification of potential drug candidates. Structure-based VS (SBVS) exploits knowledge about the three-dimensional (3D) structure of protein targets and uses the docking methodology as search engine for novel hits. The success of a SBVS campaign strongly depends upon the accuracy of the docking protocol used to select the candidates from large chemical libraries. The identification of suitable protocols is therefore a crucial step in the setup of SBVS experiments. Carrying out extensive benchmark studies, however, is usually a tangled task that requires users’ proficiency in handling different file formats and philosophies at the basis of the plethora of existing software packages. We present here DockBench 1.0, a platform available free of charge that eases the pipeline by automating the entire procedure, from docking benchmark to VS setups. In its current implementation, DockBench 1.0 handles seven docking software packages and offers the possibility to test up to seventeen different protocols. The main features of our platform are presented here and the results of the benchmark study of human Checkpoint kinase 1 (hChk1) are discussed as validation test. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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3643 KiB  
Article
S4MPLE—Sampler for Multiple Protein-Ligand Entities: Methodology and Rigid-Site Docking Benchmarking
by Laurent Hoffer, Camelia Chira, Gilles Marcou, Alexandre Varnek and Dragos Horvath
Molecules 2015, 20(5), 8997-9028; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules20058997 - 19 May 2015
Cited by 25 | Viewed by 7919
Abstract
This paper describes the development of the unified conformational sampling and docking tool called Sampler for Multiple Protein-Ligand Entities (S4MPLE). The main novelty in S4MPLE is the unified dealing with intra- and intermolecular degrees of freedom (DoF). While classically programs are either designed [...] Read more.
This paper describes the development of the unified conformational sampling and docking tool called Sampler for Multiple Protein-Ligand Entities (S4MPLE). The main novelty in S4MPLE is the unified dealing with intra- and intermolecular degrees of freedom (DoF). While classically programs are either designed for folding or docking, S4MPLE transcends this artificial specialization. It supports folding, docking of a flexible ligand into a flexible site and simultaneous docking of several ligands. The trick behind it is the formal assimilation of inter-molecular to intra-molecular DoF associated to putative inter-molecular contact axes. This is implemented within the genetic operators powering a Lamarckian Genetic Algorithm (GA). Further novelty includes differentiable interaction fingerprints to control population diversity, and fitting a simple continuum solvent model and favorable contact bonus terms to the AMBER/GAFF force field. Novel applications—docking of fragment-like compounds, simultaneous docking of multiple ligands, including free crystallographic waters—were published elsewhere. This paper discusses: (a) methodology, (b) set-up of the force field energy functions and (c) their validation in classical redocking tests. More than 80% success in redocking was achieved (RMSD of top-ranked pose < 2.0 Å). Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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1402 KiB  
Article
Development and Validation of a Docking-Based Virtual Screening Platform for the Identification of New Lactate Dehydrogenase Inhibitors
by Carlotta Granchi, Alice Capecchi, Gianluca Del Frate, Adriano Martinelli, Marco Macchia, Filippo Minutolo and Tiziano Tuccinardi
Molecules 2015, 20(5), 8772-8790; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules20058772 - 15 May 2015
Cited by 23 | Viewed by 7365
Abstract
The human muscle isoform of lactate dehydrogenase (hLDH5) is one of the key enzymes of the glycolytic process. It is overexpressed in metastatic cancer cells and is linked to the vitality of tumors in hypoxic conditions. With the aim of identifying [...] Read more.
The human muscle isoform of lactate dehydrogenase (hLDH5) is one of the key enzymes of the glycolytic process. It is overexpressed in metastatic cancer cells and is linked to the vitality of tumors in hypoxic conditions. With the aim of identifying new hLDH5 inhibitors, a fully automated docking-based virtual screening platform was developed by considering different protein conformations and the consensus docking strategy. In order to verify the reliability of the reported platform, a small database of about 10,000 compounds was filtered by using this method, and the top-ranked compounds were tested for their hLDH5 inhibition activity. Enzymatic assays revealed that, among the ten selected compounds, two proved to efficiently inhibit enzyme activity with IC50 values in the micromolar range. These results demonstrate the validity of the methodologies we followed, encouraging the application of larger virtual screening studies and further refinements of the platform. Furthermore, the two active compounds herein described may be considered as interesting leads for the development of new and more efficient LDH inhibitors. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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2414 KiB  
Article
Reduction of False Positives in Structure-Based Virtual Screening When Receptor Plasticity Is Considered
by Yaw Awuni and Yuguang Mu
Molecules 2015, 20(3), 5152-5164; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules20035152 - 19 Mar 2015
Cited by 20 | Viewed by 7599
Abstract
Structure-based virtual screening for selecting potential drug candidates is usually challenged by how numerous false positives in a molecule library are excluded when receptor plasticity is considered. In this study, based on the binding energy landscape theory, a hypothesis that a true inhibitor [...] Read more.
Structure-based virtual screening for selecting potential drug candidates is usually challenged by how numerous false positives in a molecule library are excluded when receptor plasticity is considered. In this study, based on the binding energy landscape theory, a hypothesis that a true inhibitor can bind to different conformations of the binding site favorably was put forth, and related strategies to defeat this challenge were devised; reducing false positives when receptor plasticity is considered. The receptor in the study is the influenza A nucleoprotein, whose oligomerization is a requirement for RNA binding. The structural flexibility of influenza A nucleoprotein was explored by molecular dynamics simulations. The resultant distinctive structures and the crystal structure were used as receptor models in docking exercises in which two binding sites, the tail-loop binding pocket and the RNA binding site, were targeted with the Otava PrimScreen1 diversity-molecule library using the GOLD software. The intersection ligands that were listed in the top-ranked molecules from all receptor models were selected. Such selection strategy successfully distinguished high-affinity and low-affinity control molecules added to the molecule library. This work provides an applicable approach for reducing false positives and selecting true ligands from molecule libraries. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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Review

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7136 KiB  
Review
Charting a Path to Success in Virtual Screening
by Stefano Forli
Molecules 2015, 20(10), 18732-18758; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules201018732 - 15 Oct 2015
Cited by 65 | Viewed by 10566
Abstract
Docking is commonly applied to drug design efforts, especially high-throughput virtual screenings of small molecules, to identify new compounds that bind to a given target. Despite great advances and successful applications in recent years, a number of issues remain unsolved. Most of the [...] Read more.
Docking is commonly applied to drug design efforts, especially high-throughput virtual screenings of small molecules, to identify new compounds that bind to a given target. Despite great advances and successful applications in recent years, a number of issues remain unsolved. Most of the challenges and problems faced when running docking experiments are independent of the specific software used, and can be ascribed to either improper input preparation or to the simplified approaches applied to achieve high-throughput speed. Being aware of approximations and limitations of such methods is essential to prevent errors, deal with misleading results, and increase the success rate of virtual screening campaigns. In this review, best practices and most common issues of docking and virtual screening will be discussed, covering the journey from the design of the virtual experiment to the hit identification. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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10313 KiB  
Review
Evolution of Macromolecular Docking Techniques: The Case Study of Nickel and Iron Metabolism in Pathogenic Bacteria
by Francesco Musiani and Stefano Ciurli
Molecules 2015, 20(8), 14265-14292; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules200814265 - 05 Aug 2015
Cited by 4 | Viewed by 7594
Abstract
The interaction between macromolecules is a fundamental aspect of most biological processes. The computational techniques used to study protein-protein and protein-nucleic acid interactions have evolved in the last few years because of the development of new algorithms that allow the a priori incorporation, [...] Read more.
The interaction between macromolecules is a fundamental aspect of most biological processes. The computational techniques used to study protein-protein and protein-nucleic acid interactions have evolved in the last few years because of the development of new algorithms that allow the a priori incorporation, in the docking process, of experimentally derived information, together with the possibility of accounting for the flexibility of the interacting molecules. Here we review the results and the evolution of the techniques used to study the interaction between metallo-proteins and DNA operators, all involved in the nickel and iron metabolism of pathogenic bacteria, focusing in particular on Helicobacter pylori (Hp). In the first part of the article we discuss the methods used to calculate the structure of complexes of proteins involved in the activation of the nickel-dependent enzyme urease. In the second part of the article, we concentrate on two applications of protein-DNA docking conducted on the transcription factors HpFur (ferric uptake regulator) and HpNikR (nickel regulator). In both cases we discuss the technical expedients used to take into account the conformational variability of the multi-domain proteins involved in the calculations. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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4565 KiB  
Review
Molecular Docking and Structure-Based Drug Design Strategies
by Leonardo G. Ferreira, Ricardo N. Dos Santos, Glaucius Oliva and Adriano D. Andricopulo
Molecules 2015, 20(7), 13384-13421; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules200713384 - 22 Jul 2015
Cited by 1213 | Viewed by 80743
Abstract
Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of [...] Read more.
Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of novel promising compounds. Broadly used in modern drug design, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets. This approach also estimates the ligand-receptor binding free energy by evaluating critical phenomena involved in the intermolecular recognition process. Today, as a variety of docking algorithms are available, an understanding of the advantages and limitations of each method is of fundamental importance in the development of effective strategies and the generation of relevant results. The purpose of this review is to examine current molecular docking strategies used in drug discovery and medicinal chemistry, exploring the advances in the field and the role played by the integration of structure- and ligand-based methods. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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2813 KiB  
Review
Analysis and Ranking of Protein-Protein Docking Models Using Inter-Residue Contacts and Inter-Molecular Contact Maps
by Romina Oliva, Edrisse Chermak and Luigi Cavallo
Molecules 2015, 20(7), 12045-12060; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules200712045 - 01 Jul 2015
Cited by 15 | Viewed by 9329
Abstract
In view of the increasing interest both in inhibitors of protein-protein interactions and in protein drugs themselves, analysis of the three-dimensional structure of protein-protein complexes is assuming greater relevance in drug design. In the many cases where an experimental structure is not available, [...] Read more.
In view of the increasing interest both in inhibitors of protein-protein interactions and in protein drugs themselves, analysis of the three-dimensional structure of protein-protein complexes is assuming greater relevance in drug design. In the many cases where an experimental structure is not available, protein-protein docking becomes the method of choice for predicting the arrangement of the complex. However, reliably scoring protein-protein docking poses is still an unsolved problem. As a consequence, the screening of many docking models is usually required in the analysis step, to possibly single out the correct ones. Here, making use of exemplary cases, we review our recently introduced methods for the analysis of protein complex structures and for the scoring of protein docking poses, based on the use of inter-residue contacts and their visualization in inter-molecular contact maps. We also show that the ensemble of tools we developed can be used in the context of rational drug design targeting protein-protein interactions. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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2526 KiB  
Review
Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors
by Rushikesh Sable and Seetharama Jois
Molecules 2015, 20(6), 11569-11603; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules200611569 - 23 Jun 2015
Cited by 56 | Viewed by 14603
Abstract
Blocking protein-protein interactions (PPI) using small molecules or peptides modulates biochemical pathways and has therapeutic significance. PPI inhibition for designing drug-like molecules is a new area that has been explored extensively during the last decade. Considering the number of available PPI inhibitor databases [...] Read more.
Blocking protein-protein interactions (PPI) using small molecules or peptides modulates biochemical pathways and has therapeutic significance. PPI inhibition for designing drug-like molecules is a new area that has been explored extensively during the last decade. Considering the number of available PPI inhibitor databases and the limited number of 3D structures available for proteins, docking and scoring methods play a major role in designing PPI inhibitors as well as stabilizers. Docking methods are used in the design of PPI inhibitors at several stages of finding a lead compound, including modeling the protein complex, screening for hot spots on the protein-protein interaction interface and screening small molecules or peptides that bind to the PPI interface. There are three major challenges to the use of docking on the relatively flat surfaces of PPI. In this review we will provide some examples of the use of docking in PPI inhibitor design as well as its limitations. The combination of experimental and docking methods with improved scoring function has thus far resulted in few success stories of PPI inhibitors for therapeutic purposes. Docking algorithms used for PPI are in the early stages, however, and as more data are available docking will become a highly promising area in the design of PPI inhibitors or stabilizers. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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1935 KiB  
Review
Theory and Applications of Covalent Docking in Drug Discovery: Merits and Pitfalls
by Hezekiel Mathambo Kumalo, Soumendranath Bhakat and Mahmoud E. S. Soliman
Molecules 2015, 20(2), 1984-2000; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules20021984 - 27 Jan 2015
Cited by 112 | Viewed by 16078
Abstract
he present art of drug discovery and design of new drugs is based on suicidal irreversible inhibitors. Covalent inhibition is the strategy that is used to achieve irreversible inhibition. Irreversible inhibitors interact with their targets in a time-dependent fashion, and the reaction proceeds [...] Read more.
he present art of drug discovery and design of new drugs is based on suicidal irreversible inhibitors. Covalent inhibition is the strategy that is used to achieve irreversible inhibition. Irreversible inhibitors interact with their targets in a time-dependent fashion, and the reaction proceeds to completion rather than to equilibrium. Covalent inhibitors possessed some significant advantages over non-covalent inhibitors such as covalent warheads can target rare, non-conserved residue of a particular target protein and thus led to development of highly selective inhibitors, covalent inhibitors can be effective in targeting proteins with shallow binding cleavage which will led to development of novel inhibitors with increased potency than non-covalent inhibitors. Several computational approaches have been developed to simulate covalent interactions; however, this is still a challenging area to explore. Covalent molecular docking has been recently implemented in the computer-aided drug design workflows to describe covalent interactions between inhibitors and biological targets. In this review we highlight: (i) covalent interactions in biomolecular systems; (ii) the mathematical framework of covalent molecular docking; (iii) implementation of covalent docking protocol in drug design workflows; (iv) applications covalent docking: case studies and (v) shortcomings and future perspectives of covalent docking. To the best of our knowledge; this review is the first account that highlights different aspects of covalent docking with its merits and pitfalls. We believe that the method and applications highlighted in this study will help future efforts towards the design of irreversible inhibitors. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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