Journal article
Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking
Journal of computer-aided molecular design, v 36(1), pp 25-37
2022
PMID: 34825285
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Screening already approved drugs for activity against a novel pathogen can be an important part of global rapid-response strategies in pandemics. Such high-throughput repurposing screens have already identified several existing drugs with potential to combat SARS-CoV-2. However, moving these hits forward for possible development into drugs specifically against this pathogen requires unambiguous identification of their corresponding targets, something the high-throughput screens are not typically designed to reveal. We present here a new computational inverse-docking protocol that uses all-atom protein structures and a combination of docking methods to rank-order targets for each of several existing drugs for which a plurality of recent high-throughput screens detected anti-SARS-CoV-2 activity. We demonstrate validation of this method with known drug-target pairs, including both non-antiviral and antiviral compounds. We subjected 152 distinct drugs potentially suitable for repurposing to the inverse docking procedure. The most common preferential targets were the human enzymes TMPRSS2 and PIKfyve, followed by the viral enzymes Helicase and PLpro. All compounds that selected TMPRSS2 are known serine protease inhibitors, and those that selected PIKfyve are known tyrosine kinase inhibitors. Detailed structural analysis of the docking poses revealed important insights into why these selections arose, and could potentially lead to more rational design of new drugs against these targets.
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Details
- Title
- Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking
- Creators
- Sergio R. Ribone - Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA)S. Alexis Paz - National University of CórdobaCameron F. Abrams - Drexel UniversityMarcos A. Villarreal - National University of Córdoba
- Publication Details
- Journal of computer-aided molecular design, v 36(1), pp 25-37
- Publisher
- Springer International Publishing
- Grant note
- conicet. consejo nacional de investigaciones científicas y tecnológicas universidad nacional de córdoba. argentina AI150471; GM100472 / National Institutes of Health (http://dx.doi.org/10.13039/100000002)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000722500100001
- Scopus ID
- 2-s2.0-85119868687
- Other Identifier
- 991019168301104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Biophysics
- Computer Science, Interdisciplinary Applications