Cyanobacterial metabolites as promising drug leads against the Mpro and PLpro of SARS-CoV-2: an in silico analysis

Abstract

A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged as the causative agent behind the coronavirus disease 2019 (COVID-19) pandemic. Treatment efforts have been

severely impeded due to the lack of specific effective antiviral drugs for the treatment of COVID-asso- ciated pathologies. In the present research endeavour the inhibitory prospects of cyanobacterial

metabolites were assessed at the active binding pockets of the two vital SARS-CoV-2 proteases

namely, main protease (Mpro) and the papain-like protease (PLpro) that proteolytically process viral pol- yproteins and facilitate viral replication, employing an in silico molecular interaction-based approach. It

was evident from our analysis based on the binding energy scores that the metabolites cylindrosper- mopsin, deoxycylindrospermopsin, carrageenan, cryptophycin 52, eucapsitrione, tjipanazole, tolypor- phin and apratoxin A exhibited promising inhibitory potential against the SARS-CoV-2 Mpro. The

compounds cryptophycin 1, cryptophycin 52 and deoxycylindrospermopsin were observed to display

encouraging binding energy scores with the PLpro of SARS-CoV-2. Subsequent estimation of physico- chemical properties and potential toxicity of the metabolites followed by robust molecular dynamics

simulations and analysis of MM-PBSA energy scoring function established deoxycylindrospermopsin as the most promising inhibitory candidate against both SARS-CoV-2 proteases. Present research findings bestow ample scopes to further exploit the potential of deoxycylindrospermopsin as a successful inhibitor of SARS-CoV-2 in vitro and in vivo and pave the foundation for the development of novel effective therapeutics against COVID-19.