RHAMNETIN IS A BETTER INHIBITOR OF SARS-COV-2 2'-O-METHYLTRANSFERASE THAN DOLUTEGRAVIR: A COMPUTATIONAL PREDICTION

Abstract

Background: The 2'-O-methyltransferase is responsible for the capping of SARS-CoV-2 mRNA and consequently the evasion of the host's immune system. This study aims at identifying prospective natural inhibitors of the active site of SARS-CoV-2 2'O-methyltransferase (2'-OMT) through an in silico approach.

Materials and methods: The target was docked against a library of natural compounds obtained from edible African plants using PyRx - virtual screening software. The antiviral agent, Dolutegravir which has a binding affinity score of -8.5 kcal mol^-1 with the SARS-CoV-2 2'-OMT was used as a standard. Compounds were screened for bioavailability through the SWISSADME web server using their molecular descriptors. Screenings for pharmacokinetic properties and bioactivity were performed with PKCSM and Molinspiration web servers respectively. The PLIP and Fpocket webservers were used for the binding site analyses. The Galaxy webserver was used for simulating the time-resolved motions of the apo and holo forms of the target while the MDWeb web server was used for the analyses of the trajectory data.

Results: The Root-Mean-Square-Deviation (RMSD) induced by Rhamnetin is 1.656A⁰ compared to Dolutegravir (1.579A⁰). The average B-factor induced by Rhamnetin is 113.75 while for Dolutegravir is 78.87; the Root-Mean-Square-Fluctuation (RMSF) for Rhamnetin is 0.75 and for Dolutegravir is 0.67. Also, at the active site, Rhamnetin also has a binding affinity score of -9.5 kcal mol^-1 and forms 7 hydrogen bonds compared to Dolutegravir which has -8.5 kcal mol^-1 and forms 4 hydrogen bonds respectively.

Conclusion: Rhamnetin showed better inhibitory activity at the target's active site than Dolutegravir.

Keywords: 2’-O-methyltransferase Inhibition; COVID-19; Computational Drug prediction; Coronavirus disease; SARS-CoV-2.

Figure 1

(A) the crystal structure of SARS-CoV-2 2′-OMT (cartoon model): Beta sheets in magentas, Alpha helix in cyan, and Loops in pink. (B) Surface representation of the target

Figure 2

Ramanchandran diagram of the target

Figure 3

The 3-dimensional structures of the standard and leads (stick model) (A) Dolutegravir (B) Isopteropodin (C) Rhamnetin

Figure 4

Binding site of the target interacting with the standard and leads. (a) 2’-OMT-Dolutegravir complex, (b) 2’-OMT-Isopteropodin complex (c) 2’-OMT-Rhamnetin complex