Abstract

INTRODUCTION: The binding interaction between the surface S-glycoprotein (spike protein) and angiotensin converting enzyme 2 (ACE2) membrane receptor is vital to the infectious nature of the novel SARS-Cov-2 virus. Viral variants have caused much concern as studies have associated a number of mutations with both increased viral binding affinity [1] and antibody resistance [2]. The need for novel antiviral approaches effective across all viral variants remains essential. The aim of this study is to identify drugs that bind to and maintain the S-glycoprotein in a closed conformational state thereby inhibiting viral binding to host targets. These drugs may potentially be re-purposed for the therapeutic management of COVID-19.

METHODS: In silico docking studies verified by a detailed study of the structural and molecular interaction dynamics are used to identify drugs that bind across variants of concern: B.1.1.7 (U.K. variant), B.1.351 (South African variant), and the common strain. Verified hits will be further validated for repurposing in pilot clinical studies.

RESULTS: We have identified a number of drugs that have been shown to bind to the S-glycoprotein in a closed conformational state. This was further verified and characterized across multiple variants and mutations (see figure 2 for significant mutations) of the S-glycoprotein (B.1.1.7: PDB 7LWS, B.1.351: PDB 7LYL, and common strain PDB 6VXX). Of the drugs screened we present drugs with the greatest anti-viral and anti-inflammatory potential that may be appropriately applied in a COVID setting. Among identified drugs Ivermectin was shown to have the best binding score across all variants.

CONCLUSION AND FURTHER WORK: We utilize a number of targeted in silico drug discovery approaches to identify drugs that bind the S-glycoprotein and may be repurposed to inhibit the viral-host interaction. Our study targets the viral protein in its closed conformational state and agents identified have shown binding capacity across major viral variants. Successful hits identified will be further verified using recombinant protein binding assays and may represent potential targets for preliminary clinical investigations.