Drug repurposing for SARS-COV-2: A high-throughput molecular docking, molecular dynamics, machine learning, & ab-initio study

TL;DR

This study employs a multi-scale in-silico framework combining high-throughput docking, molecular dynamics, and ab-initio methods to identify potential therapeutic ligands targeting SARS-CoV-2, analyzing over 2.2 million protein-ligand interactions.

Contribution

It introduces a comprehensive multi-step computational pipeline for screening and identifying potential drug candidates against SARS-CoV-2 from a vast compound database.

Findings

Identified three promising ligands targeting SARS-CoV-2 protein 7BV2.

Reduced candidate pool from 2.2 million to three top ligands through multi-step screening.

Validated ligand binding stability via molecular dynamics simulations.

Abstract

A molecule of dimension 125nm has caused around 479 Million human infections (80M for the USA) & 6.1 Million human deaths (977,000 for the USA) worldwide and slashed the global economy by US$ 8.5 Trillion over two years. The only other events in recent history that caused comparative human life loss through direct usage (either by (wo)man or nature, respectively) of structure-property relations of 'nano-structures' (either (wo)man-made or nature, respectively) were nuclear bomb attacks of Japanese cities by the USA during World War II and 1918 Flu Pandemic. This molecule is SARS-CoV-2, which causes a disease known as COVID-19. The high liability cost of the pandemic had incentivized various private, government, and academic entities to work towards finding a cure for these & emerging diseases. As result, multiple vaccine candidates are discovered to avoid the infection in first place. But so far, there has been no success in finding fully effective therapeutics candidates. In this paper, we attempted to provide multiple therapy candidates based upon a sophisticated multi-scale in-silico framework. We have used the following robust framework to screen the ligands; Step-I: high throughput docking, Step-II: molecular dynamics, Step-III: density functional theory analysis. In total, we have analyzed 2.2 Million unique protein binding site/ligand combinations. The proteins were selected based on recent experimental studies. Step-I had filtered that number down to 10 ligands/protein based on molecular docking binding energy, further screening down to 2 ligands/protein based on drug-likeness analysis. Additionally, these two ligands/proteins were investigated in Step-II with a molecular dynamic based RMSD analysis. It finally suggested three ligands (ZINC1176619532, ZINC517580540, ZINC952855827) attacking different binding sites of the protein(7BV2), which were further analyzed in Step III.