Repurposing drugs against main protease of SARS-CoV-2: mechanism based insights supported by available laboratory and clinical data

Abstract

<p></p><p>The ongoing global pandemic of COVID-19 has brought life to almost stand still with implementations of lockdown and social distancing as some of the preventive measures in the absence of any approved specific therapeutic interventions. To combat this crisis, research community world-wide are falling back on the existing repertoire of approved/investigational drugs to probe into their anti-coronavirus properties. In this report, we have described our unique efforts in identifying potential drugs that could be repurposed against main protease of SARS-CoV-2 (SARS-CoV-2 M<sup>pro</sup>). To achieve this goal, we have primarily exploited the principles of ‘neighbourhood behaviour’ in protein 3-D (workflow-I) and chemical 2-D structural space (workflow-II) coupled with docking simulations and insights into the possible mode of actions of the selected candidates from available literature. Such an integrative approach culminated in prioritizing 29 potential repurpose-able agents (20 approved drugs and 9 investigational molecules) against SARS-CoV-2 M<sup>pro</sup>. Apart from the approved/investigational anti-viral drugs, other notable hits include anti-bacterial, anti-inflammatory, anti-cancer and anti-coagulant drugs. Our analysis suggests that some of these drugs have the potential to simultaneously modulate the functions of viral proteins and host response system. Interestingly, many of these identified candidates (12 molecules from workflow-I and several molecules belonging to the chemical classes of alkaloids, tetracyclines, peptidomimetics from workflow-II) are suggested to possess anti-viral properties which are supported by laboratory and clinical data. Further, this work opens a new avenue of research to probe into the molecular mechanism of action of many drugs which are known to demonstrate anti-viral activity but are so far not known to target viral proteases. <b>Our findings should only be used for research purposes and we strongly urge that no individual should interpret these findings for any self-diagnosis or self-medication without the prior approval from competent international health/medical regulatory agencies.</b></p><p></p>

Lower COVID-19 mortality in Italian forested areas suggests immunoprotection by Mediterranean plants

“…We selected the docking poses with the most negative docking scores (kcal/mol) corresponding to the highest binding affinities. We validated the method applying it to other literature dockings targeting M pro , finding our binding energy scores in line with those previously reported for carnosol (Umesh et al 2020 ), apixaban and other ligands docked to the same protein target (Chakraborti et al 2020 ). The molecular graphics program incorporated in 1-Clik Mcule was used for structural visualization of protein–ligand interactions and to obtain the snapshot of Fig.…”

Haste makes waste: A critical review of docking‐based virtual screening in drug repurposing for SARS‐CoV‐2 main protease (M‐pro) inhibition

“…So, it is surprising that it is predicted to be a SARS‐CoV‐2 M‐pro inhibitor. There is no experimental evidence to suggest that remdesivir binds to SARS‐CoV‐2 M‐pro 62 . In addition, remdesivir is a prodrug, converted to its active form by host enzymes, and this was often not taken into account in the VS protocols analyzed.…”

Computational Repurposing of Drugs and Natural Products Against SARS-CoV-2 Main Protease (Mpro) as Potential COVID-19 Therapies

“…[48][49][50][51] Chakraborti et al reported the potential of ruzasvir as a drug against SARS-Cov-2, although no data were provided. 52 These drugs and natural products merit assessment in SAR-Cov-2 assays and M pro inhibition experiments.…”