Structural analysis, virtual screening and molecular simulation to identify potential inhibitors targeting 2'-O-ribose methyltransferase of SARS-CoV-2 coronavirus

Abstract

SARS-CoV-2, an emerging coronavirus, has spread rapidly around the world, resulting in over ten million cases and more than half a million deaths as of July 1, 2020. Effective treatments and vaccines for SARS-CoV-2 infection do not currently exist. Previous studies demonstrated that nonstructural protein 16 (nsp16) of coronavirus is an S-adenosyl methionine (SAM)-dependent 2'-O-methyltransferase (2'-O-MTase) that has an important role in viral replication and prevents recognition by the host innate immune system. In the present study, we employed structural analysis, virtual screening, and molecular simulation approaches to identify clinically investigated and approved drugs which can act as promising inhibitors against nsp16 2 0-O-MTase of SARS-CoV-2. Comparative analysis of primary amino acid sequences and crystal structures of seven human CoVs defined the key residues for nsp16 2-O'-MTase functions. Virtual screening and docking analysis ranked the potential inhibitors of nsp16 from more than 4,500 clinically investigated and approved drugs. Furthermore, molecular dynamics simulations were carried out on eight top candidates, including Hesperidin, Rimegepant, Gs-9667, and Sonedenoson, to calculate various structural parameters and understand the dynamic behavior of the drug-protein complexes. Our studies provided the foundation to further test and repurpose these candidate drugs experimentally and/or clinically for COVID-19 treatment.

Molecular Simulation-Based Investigation of Highly Potent Natural Products to Abrogate Formation of the nsp10–nsp16 Complex of SARS-CoV-2

“…In a recent in silico study, a range of compounds was tested against the stimulatory factor of MTase-nsp10–nsp16 complex of SARS-CoV-2 [ 30 ]. Moreover, recent structural analysis studies presented the importance of 2′-O-MTase nsp16 of SARS-CoV-2 as a drug target [ 31 , 32 ]. Nsp10 residues 42–120 were shown to be the functional area required for stimulating nsp16 enzymatic activity [ 28 ].…”

Energy and Reactivity Profile and Proton Affinity Analysis of Rimegepant with Special Reference to its Potential Activity against SARS-Cov-2 Virus Proteins using Molecular Dynamics

“…Also, we wanted to check whether this new drug is a probable candidate for drug repurposing for the management of the COVID-19. Jiang and co-workers already showed that this molecule is a potential inhibitors targeting 2'-O-ribose methyltransferase of SARS-CoV-2 [24]. In this manuscript, we report the structure and electronic features of this molecule and also molecular docking and molecular dynamics study of the compound was performed with three other established COVID protein targets.…”

The Role of Coronavirus RNA-Processing Enzymes in Innate Immune Evasion

“…The design of SAM analogues that also interacts with this adjacent cap-binding site is a challenge for the generation of more potent and specific inhibitors compared to sinefungin [ 115 , 119 ]. In this direction, several groups have performed virtual screening and molecular docking in order to identify alternative candidate drugs [ 120 , 121 , 122 ].…”