Identification of 4-acrylamido-N-(pyridazin-3-yl)benzamide as anti-COVID-19 compound: a DFTB, molecular docking, and molecular dynamics study.

Abstract

Omicron is one of the variants of COVID-19 and continuing member of a pandemic. There are several types of vaccines that were developed around the globe to fight against the virus. However, the world is suffering to find suitable drug candidates for the virus. The main protease (Mpro) enzyme of the virus is the best target for finding drug molecules because of its involvement in viral infection and protein synthesis. ZINC-15 is a database of 750 million commercially available compounds. We find 125 compounds having two aromatic rings and amide groups for non-covalent interactions with active site amino acids and functional groups with the capability to bind –SH group of C145 of Mpro through covalent bonding by a nucleophilic addition reaction. The lead compound (Z144) was identified using molecular docking. The non-covalent interactions (NCI) calculations show the interactions between amino acids present in the active site of the protein and the lead molecules are attractive in nature. The density functional-based tight-binding (DFTB) study of the lead compound with amino acids in the active site indicates that Q190 and Q193 play a very critical role in stabilization. The Michael addition of the acrylamide group of the lead molecule at β-position is facile because the low energy lowest unoccupied molecular orbital (LUMO) is concentrated on the group. From molecular dynamics during 100 ns, it has come to light that strong non-covalent interactions are key for the stability of the lead inside the protein and such binding can fold the protein. The free energy for this interaction is −42.72 kcal mol−1 which was obtained from MM-GB/SA calculations.