Abstract
Novel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (Mpro) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify Mpro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with Mpro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 Mpro inhibitors.
Highlights
SARS-CoV-2, the causative agent of Coronavirus disease (COVID-19), created havoc globally by infecting the large Human population and tremendously impacting the public health care system by its first outbreak in the form of pneumonia cluster in the Wuhan Province of China on 17/11/2019 and subsequent spread of COVID-19 w orldwide[1,2]
The unavailability of a more effective drug has already exacerbated the condition of COVID-19 pandemic
Several efforts are being made to target the first step of viral invasion and infection of SARS-CoV-2 enabled by the molecular interactions between human Angiotensin-converting enzyme 2 and CoV-2 spike proteins
Summary
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the causative agent of Coronavirus disease (COVID-19), created havoc globally by infecting the large Human population and tremendously impacting the public health care system by its first outbreak in the form of pneumonia cluster in the Wuhan Province of China on 17/11/2019 and subsequent spread of COVID-19 w orldwide[1,2]. Remarkable progress have been made to design and develop new vaccines improving the immune response to SARS-CoV-2 and its select s trains[33] These include encapsulated RNA-based vaccine (mRNA-1273, Moderna)[34], non-replicating viral vector (Sputnik V, Gamaleya; AZD1222, Oxford/AstraZeneca)[35,36] and inactivated viral vaccine (Covaxin, Bharat Biotech)[37]. We performed a computational approach to identify Mpro inhibitors from a compiled library of antiviral small molecules[39,40] using a hierarchical workflow of structure-based virtual screening, dynamic simulations and binding free energy calculations
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