Targeting the Coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors Lopinavir, Ritonavir, and Nelfinavir.
Giovanni Bolcato, Maicol Bissaro, Matteo Pavan, Mattia Sturlese, Stefano Moro
Received date: 11th March 2020
Coronavirus SARS-CoV-2 is a recently discovered single-stranded RNA (ssRNA) betacoronavirus, responsible for a severe respiratory disease known as coronavirus disease 2019 (COVID-19), which is rapidly spreading. Chinese health authorities, as a response to the lack of an effective therapeutic strategy, started to investigate the use of lopinavir and ritonavir, previously optimized for the treatment and prevention of HIV/AIDS viral infection. Despite the clinical use of these two drugs, no information regarding their possible mechanism of action at the molecular level is still known for SARS-CoV-2. Very recently, the crystallographic structure of the SARS-CoV-2 main protease (Mpro), also known as C30 Endopeptidase, was published. Starting from this essential structural information, in the present work we have exploited Supervised Molecular Dynamics (SuMD), an emerging computational technique that allows investigating at an atomic level the recognition process of a ligand from its unbound to the final bound state. In this research, we provided molecular insight on the whole interaction pathway of lopinavir, ritonavir, and nelfinavir, three potential C30 Endopeptidase inhibitors, with the last one taken into consideration due to the promising in-vitro activity shown against the structurally related SARS-CoV protease.
This is an abstract of a preprint hosted on a preprint server, which is currently undergoing peer review at Scientific Reports. The findings have yet to be thoroughly evaluated, nor has a decision on ultimate publication been made. Therefore, the results reported should not be considered conclusive, and these findings should not be used to inform clinical practice, or public health policy, or be promoted as verified information.