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

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 ^pro ). 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 ^pro . 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. 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.