A COVID-19 Drug Repurposing Strategy through Quantitative Homological Similarities Using a Topological Data Analysis-Based Framework.

Jean-Louis Duval,Jaume Forés-Martos,Joan Climent,Beatriz Suay-García,Antonio Falcó,Raul Pérez-Moraga

doi:10.3390/pharmaceutics13040488

Abstract

Since its emergence in March 2020, the SARS-CoV-2 global pandemic has produced more than 116 million cases and 2.5 million deaths worldwide. Despite the enormous efforts carried out by the scientific community, no effective treatments have been developed to date. We applied a novel computational pipeline aimed to accelerate the process of identifying drug repurposing candidates which allows us to compare three-dimensional protein structures. Its use in conjunction with two in silico validation strategies (molecular docking and transcriptomic analyses) allowed us to identify a set of potential drug repurposing candidates targeting three viral proteins (3CL viral protease, NSP15 endoribonuclease, and NSP12 RNA-dependent RNA polymerase), which included rutin, dexamethasone, and vemurafenib. This is the first time that a topological data analysis (TDA)-based strategy has been used to compare a massive number of protein structures with the final objective of performing drug repurposing to treat SARS-CoV-2 infection.

Highlights

The RNA-dependent RNA polymerase was found to be significantly associated with 361 Protein Data Bank (PDB) structures (Supplementary Table S3), which in many cases belonged to the protein kinase and flavin-containing oxidoreductase families, and that were found to be targeted by 204 unique drugs (Supplementary Table S4)
As specific antiviral treatments are still under development and the vaccination campaign has faced difficulties derived from unmet forecasts in the process of production and distribution, drug repurposing strategies suggesting the use of FDA-approved drugs continue to be a valuable option to find candidate drugs for the effective treatment of COVID-19 in a short timeframe
The result of the possible interaction between rutin and 3CL protease has been reported by other studies using an in silico approach [53], our results provide a transcriptomic dimension to the possible effect of rutin during infection with SARS-CoV-2

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. On 11 March 2020, the World Health Organization (WHO) declared the Coronavirus. Disease 2019 (COVID-19) outbreak, produced by the novel SARS-CoV-2 virus, a global pandemic [1]. Three previously approved antiviral drugs and one antimalarial medication (remdesevir, iopinavir, interferon-1, and hydroxychloroquine) have been tested for efficacy against SARS-CoV-2 infection by the WHO SOLIDARITY consortium in a large multicentric study. The results of the trial suggested that these treatments had little or no effect in a set of clinical outcomes which included overall mortality, time to initiation of mechanical ventilation, and duration of hospital stay [2]

Methods

Findings

Discussion

Conclusion