β-amino alcohols as promising inhibitory candidates against the SARS-CoV-2, A theoretical design based on MD simulation and DFT insights

Abstract

Nelfinavir, as a compound with a Chiral β-amino alcohol unit, is a well-known inhibitor against HIV-protease, studying. The role of heterocyclic derivatives of Nelfinavir as inhibitors against the Main-Protease of COVID-19 is the main purpose of this study. To reach a deep understanding, different theoretical approaches including molecular docking, Molecular Dynamic (MD) simulations, and DFT insights are applied in the studies. Investigation of the ligand bioactivity reveals that smaller HOMO/LUMO band gaps and lower chemical hardness (η), mean stronger interaction with the active site of the Main-Protease for the corresponding β-amino alcohols. Analyzing the efficient interactions in binding energy shows that among the studied Chiral β-amino alcohols, formed Van der Waals interactions via π and alkyl parts of ligands have more remarkable roles in inhibitory effects than hydrogen bonding. Accordingly, molecular mechanics (MM) and polar interactions have the highest contributions to the total energy of residues. Finally, it has been concluded that among the studied derivatives those that contain Dihydroisoquinoline (4b), and Perhydroisoquinoline (4d) heterocyclic rings can be considered as more potent candidates against Main-Protease of COVID-19.