Abstract
Coronavirus SARS-CoV-2 is a recently discovered single-stranded RNA betacoronavirus, responsible for a severe respiratory disease known as coronavirus disease 2019, 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, 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 recognition 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.
Highlights
Coronavirus SARS-CoV-2, previously known as 2019-nCoV, is a recently discovered single-stranded RNA betacoronavirus, responsible for a severe pathological condition known as coronavirus disease 2019 (COVID-19)[1]
In the last two decades, three major outbreaks of coronavirus-related diseasesSARS-CoV, MERS-CoV and ultimatelySARS-CoV-2 have been responsible for significant public health issues, along with dramatic socialeconomic consequences
The process of drug discovery often undergoes timelines which are difficult to reconcile with the urgency and the need to provide an effective therapeutic response to such an emergency health situation
Summary
Coronavirus SARS-CoV-2, previously known as 2019-nCoV, is a recently discovered single-stranded RNA (ssRNA) betacoronavirus, responsible for a severe pathological condition known as coronavirus disease 2019 (COVID-19)[1] Since it was first identified in December 2019, this novel coronavirus has rapidly spread all around the world, being since responsible for the death of more than one million of people, which have lost their lives due to a severe respiratory illness[2]. The early isolation of the SARS-CoV-2 genome from ill patients represented a first crucial outcome, making it possible to highlight an important sequence identity (~ 80% of conserved nucleotides) with respect to the original SARS-CoV epidemic virus[6] In light of this similarity, some therapeutic strategies could be inherited from other genetically related CoV diseases. The development of a vaccine is desirable, and it is foreseen that the first candidates will be advanced to clinical phase I around mid-20207–9
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