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Recent Advances in Virtual Screening
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Recent Advances in Virtual Screening

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

Deadline for manuscript submissions: closed (15 August 2019) | Viewed by 39583

Special Issue Editor

Dr. Gerard Pujadas

E-Mail Website
Guest Editor
Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Catalonia, Spain
Interests: drug discovery; drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Finding new leads is an essential step in projects to develop and discover new drugs. There are two alternatives for achieving this goal: (a) experimentally testing compound libraries to find molecules that show any level of the desired bioactivity (a process known as high throughput screening⁠) and (b) a cheaper alternative that aims to computationally predict the bioactivity of interest in files containing molecular databases (known as virtual screening, VS). This Special Issue of IJMS will focus on recent advances in VS with particular emphasis on tools (either local or on-line) or databases that can be used for free for non-profit research or education.

Dr. Gerard Pujadas
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • drug discovery
  • protein-ligand docking
  • pharmacophore screening
  • lead discovery
  • molecular databases
  • bioactivity prediction

Published Papers (7 papers)

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Research

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15 pages, 2192 KiB  
Article
A Free Web-Based Protocol to Assist Structure-Based Virtual Screening Experiments
by Nathalie Lagarde, Elodie Goldwaser, Tania Pencheva, Dessislava Jereva, Ilza Pajeva, Julien Rey, Pierre Tuffery, Bruno O. Villoutreix and Maria A. Miteva
Int. J. Mol. Sci. 2019, 20(18), 4648; https://doi.org/10.3390/ijms20184648 - 19 Sep 2019
Cited by 16 | Viewed by 5437
Abstract
Chemical biology and drug discovery are complex and costly processes. In silico screening approaches play a key role in the identification and optimization of original bioactive molecules and increase the performance of modern chemical biology and drug discovery endeavors. Here, we describe a [...] Read more.
Chemical biology and drug discovery are complex and costly processes. In silico screening approaches play a key role in the identification and optimization of original bioactive molecules and increase the performance of modern chemical biology and drug discovery endeavors. Here, we describe a free web-based protocol dedicated to small-molecule virtual screening that includes three major steps: ADME-Tox filtering (via the web service FAF-Drugs4), docking-based virtual screening (via the web service MTiOpenScreen), and molecular mechanics optimization (via the web service AMMOS2 [Automatic Molecular Mechanics Optimization for in silico Screening]). The online tools FAF-Drugs4, MTiOpenScreen, and AMMOS2 are implemented in the freely accessible RPBS (Ressource Parisienne en Bioinformatique Structurale) platform. The proposed protocol allows users to screen thousands of small molecules and to download the top 1500 docked molecules that can be further processed online. Users can then decide to purchase a small list of compounds for in vitro validation. To demonstrate the potential of this online-based protocol, we performed virtual screening experiments of 4574 approved drugs against three cancer targets. The results were analyzed in the light of published drugs that have already been repositioned on these targets. We show that our protocol is able to identify active drugs within the top-ranked compounds. The web-based protocol is user-friendly and can successfully guide the identification of new promising molecules for chemical biology and drug discovery purposes. Full article
(This article belongs to the Special Issue Recent Advances in Virtual Screening)
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17 pages, 3579 KiB  
Article
Identification of Functional and Druggable Sites in Aspergillus fumigatus Essential Phosphatases by Virtual Screening
by Benjamin P. Thornton, Anna Johns, Reem Al-Shidhani, Sandra Álvarez-Carretero, Isabelle S. R. Storer, Michael J. Bromley and Lydia Tabernero
Int. J. Mol. Sci. 2019, 20(18), 4636; https://doi.org/10.3390/ijms20184636 - 19 Sep 2019
Cited by 6 | Viewed by 3940
Abstract
Fungal diseases are a serious health burden worldwide with drug resistance compromising efficacy of the limited arsenal of antifungals available. New drugs with novel mechanisms of action are desperately needed to overcome current challenges. The screening of the Aspergillus fumigatus genome identified 35 [...] Read more.
Fungal diseases are a serious health burden worldwide with drug resistance compromising efficacy of the limited arsenal of antifungals available. New drugs with novel mechanisms of action are desperately needed to overcome current challenges. The screening of the Aspergillus fumigatus genome identified 35 phosphatases, four of which were previously reported as essential for viability. In addition, we validated another three essential phosphatases. Phosphatases control critical events in fungi from cell wall integrity to cell cycle, thus they are attractive targets for drug development. We used VSpipe v1.0, a virtual screening pipeline, to evaluate the druggability of the seven essential phosphatases and identify starting points for drug discovery. Targeted virtual screening and evaluation of the ligand efficiency plots created by VSpipe, enabled us to define the most favourable chemical space for drug development and suggested different modes of inhibition for each phosphatase. Interestingly, the identified ligand binding sites match with functional sites (active site and protein interaction sites) reported for other yeast and human homologues. Thus, the VSpipe virtual screening approach identified both druggable and functional sites in these essential phosphatases for further experimental validation and antifungal drug development. Full article
(This article belongs to the Special Issue Recent Advances in Virtual Screening)
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25 pages, 7919 KiB  
Article
A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening
by Mira Ahinko, Sami T. Kurkinen, Sanna P. Niinivehmas, Olli T. Pentikäinen and Pekka A. Postila
Int. J. Mol. Sci. 2019, 20(11), 2779; https://doi.org/10.3390/ijms20112779 - 06 Jun 2019
Cited by 9 | Viewed by 4566
Abstract
Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein’s ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB [...] Read more.
Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein’s ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening. This cavity-based rigid docking has been demonstrated to work with genuine drug targets in both benchmark testing and drug candidate/lead discovery. Firstly, the study explores in-depth the applicability of different ligand 3D conformer generation software for acquiring the best NIB screening results using cyclooxygenase-2 (COX-2) as the example system. Secondly, the entire NIB workflow from the protein structure preparation, model build-up, and ligand conformer generation to the similarity comparison is performed for COX-2. Accordingly, hands-on instructions are provided on how to employ the NIB methodology from start to finish, both with the rigid docking and docking rescoring using noncommercial software. The practical aspects of the NIB methodology, especially the effect of ligand conformers, are discussed thoroughly, thus, making the methodology accessible for new users. Full article
(This article belongs to the Special Issue Recent Advances in Virtual Screening)
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19 pages, 10819 KiB  
Article
Discovery of High Affinity Receptors for Dityrosine through Inverse Virtual Screening and Docking and Molecular Dynamics
by Fangfang Wang, Wei Yang and Xiaojun Hu
Int. J. Mol. Sci. 2019, 20(1), 115; https://doi.org/10.3390/ijms20010115 - 29 Dec 2018
Cited by 24 | Viewed by 5073
Abstract
Dityrosine is the product of oxidation that has been linked to a number of serious pathological conditions. Evidence indicates that high amounts of dityrosine exist in oxidized milk powders and some milk related foodstuffs, further reducing the nutritional value of oxidized proteins. Therefore, [...] Read more.
Dityrosine is the product of oxidation that has been linked to a number of serious pathological conditions. Evidence indicates that high amounts of dityrosine exist in oxidized milk powders and some milk related foodstuffs, further reducing the nutritional value of oxidized proteins. Therefore, we hypothesize that some receptors related to special diseases would be targets for dityrosine. However, the mechanisms of the interaction of dityrosine with probable targets are still unknown. In the present work, an inverse virtual screening approach was performed to screen possible novel targets for dityrosine. Molecular docking studies were performed on a panel of targets extracted from the potential drug target database (PDTD) to optimize and validate the screening results. Firstly, two different conformations cis- and trans- were found for dityrosine during minimization. Moreover, Tubulin (αT) (−11.0 kcal/mol) was identified as a target for cis-dityrosine (CDT), targets including αT (−11.2 kcal/mol) and thyroid hormone receptor beta-1 (−10.7 kcal/mol) presented high binding affinities for trans-dityrosine (TDT). Furthermore, in order to provide binding complexes with higher precision, the three docked systems were further refined by performing thermo dynamic simulations. A series of techniques for searching for the most stable binding pose and the calculation of binding free energy are elaborately provided in this work. The major interactions between these targets and dityrosine were hydrophobic, electrostatic and hydrogen bonding. The application of inverse virtual screening method may facilitate the prediction of unknown targets for known ligands, and direct future experimental assays. Full article
(This article belongs to the Special Issue Recent Advances in Virtual Screening)
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Review

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12 pages, 1368 KiB  
Review
Application of the SwissDrugDesign Online Resources in Virtual Screening
by Antoine Daina and Vincent Zoete
Int. J. Mol. Sci. 2019, 20(18), 4612; https://doi.org/10.3390/ijms20184612 - 18 Sep 2019
Cited by 54 | Viewed by 5179
Abstract
SwissDrugDesign is an important initiative led by the Molecular Modeling Group of the SIB Swiss Institute of Bioinformatics. This project provides a collection of freely available online tools for computer-aided drug design. Some of these web-based methods, i.e., SwissSimilarity and SwissTargetPrediction, were especially [...] Read more.
SwissDrugDesign is an important initiative led by the Molecular Modeling Group of the SIB Swiss Institute of Bioinformatics. This project provides a collection of freely available online tools for computer-aided drug design. Some of these web-based methods, i.e., SwissSimilarity and SwissTargetPrediction, were especially developed to perform virtual screening, while others such as SwissADME, SwissDock, SwissParam and SwissBioisostere can find applications in related activities. The present review aims at providing a short description of these methods together with examples of their application in virtual screening, where SwissDrugDesign tools successfully supported the discovery of bioactive small molecules. Full article
(This article belongs to the Special Issue Recent Advances in Virtual Screening)
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19 pages, 3506 KiB  
Review
Emerging Screening Approaches in the Development of Nrf2–Keap1 Protein–Protein Interaction Inhibitors
by Chung-Hang Leung, Jia-Tong Zhang, Guan-Jun Yang, Hao Liu, Quan-Bin Han and Dik-Lung Ma
Int. J. Mol. Sci. 2019, 20(18), 4445; https://doi.org/10.3390/ijms20184445 - 10 Sep 2019
Cited by 39 | Viewed by 5836
Abstract
Due to role of the Keap1–Nrf2 protein–protein interaction (PPI) in protecting cells from oxidative stress, the development of small molecule inhibitors that inhibit this interaction has arisen as a viable approach to combat maladies caused by oxidative stress, such as cancers, neurodegenerative disease [...] Read more.
Due to role of the Keap1–Nrf2 protein–protein interaction (PPI) in protecting cells from oxidative stress, the development of small molecule inhibitors that inhibit this interaction has arisen as a viable approach to combat maladies caused by oxidative stress, such as cancers, neurodegenerative disease and diabetes. To obtain specific and genuine Keap1–Nrf2 inhibitors, many efforts have been made towards developing new screening approaches. However, there is no inhibitor for this target entering the clinic for the treatment of human diseases. New strategies to identify novel bioactive compounds from large molecular databases and accelerate the developmental process of the clinical application of Keap1–Nrf2 protein–protein interaction inhibitors are greatly needed. In this review, we have summarized virtual screening and other methods for discovering new lead compounds against the Keap1–Nrf2 protein–protein interaction. We also discuss the advantages and limitations of different strategies, and the potential of this PPI as a drug target in disease therapy. Full article
(This article belongs to the Special Issue Recent Advances in Virtual Screening)
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24 pages, 1829 KiB  
Review
The Light and Dark Sides of Virtual Screening: What Is There to Know?
by Aleix Gimeno, María José Ojeda-Montes, Sarah Tomás-Hernández, Adrià Cereto-Massagué, Raúl Beltrán-Debón, Miquel Mulero, Gerard Pujadas and Santiago Garcia-Vallvé
Int. J. Mol. Sci. 2019, 20(6), 1375; https://doi.org/10.3390/ijms20061375 - 19 Mar 2019
Cited by 154 | Viewed by 8614
Abstract
Virtual screening consists of using computational tools to predict potentially bioactive compounds from files containing large libraries of small molecules. Virtual screening is becoming increasingly popular in the field of drug discovery as in silico techniques are continuously being developed, improved, and made [...] Read more.
Virtual screening consists of using computational tools to predict potentially bioactive compounds from files containing large libraries of small molecules. Virtual screening is becoming increasingly popular in the field of drug discovery as in silico techniques are continuously being developed, improved, and made available. As most of these techniques are easy to use, both private and public organizations apply virtual screening methodologies to save resources in the laboratory. However, it is often the case that the techniques implemented in virtual screening workflows are restricted to those that the research team knows. Moreover, although the software is often easy to use, each methodology has a series of drawbacks that should be avoided so that false results or artifacts are not produced. Here, we review the most common methodologies used in virtual screening workflows in order to both introduce the inexperienced researcher to new methodologies and advise the experienced researcher on how to prevent common mistakes and the improper usage of virtual screening methodologies. Full article
(This article belongs to the Special Issue Recent Advances in Virtual Screening)
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