Not One, But Five: Virtual Screening-Driven Drug Discovery of SARS-CoV2 Enzyme Inhibitors Targeting Viral Attachment, Replication and Post-Translational Infection Mechanisms

Abstract

The novel coronavirus SARS-CoV2, the causative agent of the worldwide pandemic disease COVID-19, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths worldwide have necessitated the need to discover substances that can be tapped for drug development. With the aid of bioinformatics and computational modelling, ninety seven secondary metabolites from fungi previously reported to exhibit antiviral properties were docked onto SARS-CoV2 enzymes involved in viral attachment, replication and post-translational mechanisms followed by <i>in silico</i> ADMET prediction (absorption, distribution, metabolism, excretion and toxicity) of the hit compounds. Thus, two fumiquinazoline alkaloids quinadoline B (<b>19</b>), scedapin C (<b>15</b>), and the polyketide isochaetochromin D1 (<b>8</b>) exhibited high binding affinities depending on the target protein. The compounds were active against the cysteine proteases, papain-like protease (PLpro) and chymotrypsin-like protease (3CLpro) which are involved in post-translational modifications, RNA-directed RNA polymerase (RdRp) which is essential in viral replication, non-structural protein 15 (nsp15) which is involved in evasion of host immunity, and the spike protein which is responsible for binding to GRP78. Quinadoline B (<b>19</b>) was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.