Investigation of bio-active Amaryllidaceae alkaloidal small molecules as putative SARS-CoV-2 main protease and host TMPRSS2 inhibitors: interpretation by in-silico simulation study

The novel coronavirus disease 2019 (Covid-19) outburst is still threatening global health. This highly contagious viral disease is caused by the infection of SARS-CoV-2 virus. Covid-19 and post-Covid-19 complications induce noteworthy mortality. Potential chemical hits and leads against SARS-CoV-2 for combating Covid-19 are urgently required. In the present study, a virtual-screening protocol was executed on potential Amaryllidaceae alkaloids from a pool of natural compound library against SARS-CoV-2 main protease (M-pro) and transmembrane serine protease (TMPRSS2). For the collected 1016 alkaloids from the curated library, initially, molecular docking using AutoDock Vina (ADV), and thereafter 100 ns molecular-dynamic (MD) simulation has been executed for the best top-ranked binding affinity compounds for both the viral and host proteins. Comprehensive intermolecular-binding interactions profile of Amaryllidaceae alkaloids suggested that phyto-compounds Galantamine, Lycorenine, and Neronine as potent modulators of SARS-CoV-2 M-pro and host TMPRSS2 protein. All atomistic long range 100 ns MD simulation studies of each top ranked complex in triplicates also illustrated strong binding affinity of three compounds towards M-pro and TMPRSS2. Identified compounds might be recommended as prospective anti-viral agents for future drug development selectively targeting the SARS-CoV-2 M-pro or blocking host TMPRSS2 receptor, subjected to pre-clinical and clinical assessment for a better understanding of in-vitro molecular interaction and in-vivo validation.Communicated by Ramaswamy H. Sarma