A Systematic Review of Computational Drug Discovery, Development, and Repurposing for Ebola Virus Disease Treatment

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Abstract

Ebola virus disease (EVD) is a deadly global public health threat, with no currently approved treatments. Traditional drug discovery and development is too expensive and inefficient to react quickly to the threat. We review published research studies that utilize computational approaches to find or develop drugs that target the Ebola virus and synthesize its results. A variety of hypothesized and/or novel treatments are reported to have potential anti-Ebola activity. Approaches that utilize multi-targeting/polypharmacology have the most promise in treating EVD.

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Structure validation by Calpha geometry: phi,psi and Cbeta deviation.

Simon C. Lovell, Ian W. Davis, W Bryan Arendall … (2003)

Geometrical validation around the Calpha is described, with a new Cbeta measure and updated Ramachandran plot. Deviation of the observed Cbeta atom from ideal position provides a single measure encapsulating the major structure-validation information contained in bond angle distortions. Cbeta deviation is sensitive to incompatibilities between sidechain and backbone caused by misfit conformations or inappropriate refinement restraints. A new phi,psi plot using density-dependent smoothing for 81,234 non-Gly, non-Pro, and non-prePro residues with B < 30 from 500 high-resolution proteins shows sharp boundaries at critical edges and clear delineation between large empty areas and regions that are allowed but disfavored. One such region is the gamma-turn conformation near +75 degrees,-60 degrees, counted as forbidden by common structure-validation programs; however, it occurs in well-ordered parts of good structures, it is overrepresented near functional sites, and strain is partly compensated by the gamma-turn H-bond. Favored and allowed phi,psi regions are also defined for Pro, pre-Pro, and Gly (important because Gly phi,psi angles are more permissive but less accurately determined). Details of these accurate empirical distributions are poorly predicted by previous theoretical calculations, including a region left of alpha-helix, which rates as favorable in energy yet rarely occurs. A proposed factor explaining this discrepancy is that crowding of the two-peptide NHs permits donating only a single H-bond. New calculations by Hu et al. [Proteins 2002 (this issue)] for Ala and Gly dipeptides, using mixed quantum mechanics and molecular mechanics, fit our nonrepetitive data in excellent detail. To run our geometrical evaluations on a user-uploaded file, see MOLPROBITY (http://kinemage.biochem.duke.edu) or RAMPAGE (http://www-cryst.bioc.cam.ac.uk/rampage). Copyright 2003 Wiley-Liss, Inc.

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TCM Database@Taiwan: The World's Largest Traditional Chinese Medicine Database for Drug Screening In Silico

Calvin Yu-Chian Chen (2011)

Rapid advancing computational technologies have greatly speeded up the development of computer-aided drug design (CADD). Recently, pharmaceutical companies have increasingly shifted their attentions toward traditional Chinese medicine (TCM) for novel lead compounds. Despite the growing number of studies on TCM, there is no free 3D small molecular structure database of TCM available for virtual screening or molecular simulation. To address this shortcoming, we have constructed TCM Database@Taiwan (http://tcm.cmu.edu.tw/) based on information collected from Chinese medical texts and scientific publications. TCM Database@Taiwan is currently the world's largest non-commercial TCM database. This web-based database contains more than 20,000 pure compounds isolated from 453 TCM ingredients. Both cdx (2D) and Tripos mol2 (3D) formats of each pure compound in the database are available for download and virtual screening. The TCM database includes both simple and advanced web-based query options that can specify search clauses, such as molecular properties, substructures, TCM ingredients, and TCM classification, based on intended drug actions. The TCM database can be easily accessed by all researchers conducting CADD. Over the last eight years, numerous volunteers have devoted their time to analyze TCM ingredients from Chinese medical texts as well as to construct structure files for each isolated compound. We believe that TCM Database@Taiwan will be a milestone on the path towards modernizing traditional Chinese medicine.

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Multi-target therapeutics: when the whole is greater than the sum of the parts.

Grant Zimmermann, Joseph Lehár, Curtis Keith (2007)

Drugs designed to act against individual molecular targets cannot usually combat multigenic diseases such as cancer, or diseases that affect multiple tissues or cell types such as diabetes and immunoinflammatory disorders. Combination drugs that impact multiple targets simultaneously are better at controlling complex disease systems, are less prone to drug resistance and are the standard of care in many important therapeutic areas. The combination drugs currently employed are primarily of rational design, but the increased efficacy they provide justifies in vitro discovery efforts for identifying novel multi-target mechanisms. In this review, we discuss the biological rationale for combination therapeutics, review some existing combination drugs and present a systematic approach to identify interactions between molecular pathways that could be leveraged for therapeutic benefit.

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Journal

Journal ID (nlm-ta): Molecules

Journal ID (iso-abbrev): Molecules

Journal ID (publisher-id): molecules

Title: Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry

Publisher: MDPI

ISSN (Electronic): 1420-3049

Publication date (Electronic): 20 October 2017

Publication date Collection: October 2017

Volume: 22

Issue: 10

Electronic Location Identifier: 1777

Affiliations

Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14203, USA; jcschule@ 123456buffalo.edu (J.S.); mlhudson@ 123456buffalo.edu (M.L.H.); digs@ 123456buffalo.edu (D.S.)

Author notes

[* ]Correspondence: ram@ 123456compbio.org ; Tel.: +1-414-367-7267

[†]

These authors contributed equally to this work.

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Publisher ID: molecules-22-01777

DOI: 10.3390/molecules22101777

PMC ID: 6151658

PubMed ID: 29053626

SO-VID: d85052d2-77b7-4fe5-b8ba-af8a6e009afb

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

A Systematic Review of Computational Drug Discovery, Development, and Repurposing for Ebola Virus Disease Treatment

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Most cited references 89

Structure validation by Calpha geometry: phi,psi and Cbeta deviation.

TCM Database@Taiwan: The World's Largest Traditional Chinese Medicine Database for Drug Screening In Silico

Multi-target therapeutics: when the whole is greater than the sum of the parts.

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