Pharmacophore based virtual screening for natural product database revealed possible inhibitors for SARS-COV-2 main protease

Abstract

The challenge continues globally triggered by the absence of an approved antiviral drug against COVID-19 virus infection necessitating global concerted efforts of scientists. Nature still provides a renewable source for drugs used to solve many health problems. The aim of this work is to provide new candidates from natural origin to overcome COVID-19 pandemic. A virtual screening of the natural compounds database (47,645 compounds) using structure-based pharmacophore model and molecular docking simulations reported eight hits from natural origin against SARS-CoV-2 main proteinase (Mpro) enzyme. The successful candidates were of terpenoidal nature including taxusabietane, Isoadenolin A & C, Xerophilusin B, Excisanin H, Macrocalin B and ponicidin, phytoconstituents isolated from family Lamiaceae and sharing a common ent-kaurane nucleus, were found to be the most successful candidates. This study suggested that the diterpene nucleus has a clear positive contribution which can represent a new opportunity in the development of SARS-CoV-2 main protease inhibitors.

Keywords: COVID-19; Ent-kaurane; Main protease inhibitors; Pharmacophore; Terpenoids.

Graphical abstract

Fig. 1

Pharmacophoric features for SARS-COV-2 main protease enzyme (ligand-based pharmacophore).

Fig. 2

Superimposition of selected hits on pharmacophoric features.

Fig. 3

2D interactions of X77 within SARS-COV-2 main protease active site.

Fig. 4

3D representation of the superimposition of the co-crystallized (red) and the docking pose (green) of X77 in the SARS-COV-2 main protease active site.

Fig. 5

3D interactions of the selected docked compounds in the SARS-COV-2 main protease active site a) NPC157929, b) NPC309388, c) NPC17165, d) NPC94141, e) NPC184170, f) NPC107385, g) NPC470166, h) NPC472282.

Fig. 5

3D interactions of the selected docked compounds in the SARS-COV-2 main protease active site a) NPC157929, b) NPC309388, c) NPC17165, d) NPC94141, e) NPC184170, f) NPC107385, g) NPC470166, h) NPC472282.

Fig. 6

RMSD plot of the protein (black), NPC472282 (red), NPC184170 (green) and NPC107385 (blue) and X77 (yellow) for 100 ns MD simulation.

Fig. 7

The number of hydrogen bonds calculated over 100 ns molecular dynamics, where NPC472282 is shown in black, NPC184170 in red and NPC107385 in green.