Available online 23 December 2021

Rapidly evolving COVID-19 pandemic demands the discovery of effective antiviral drugs.

DFT is extensively applied in molecular modeling studies of COVID-19 pharmaceuticals.

DFT is used as a stand-alone method for electronic structure calculations of drug compounds.

Molecular mechanics techniques and DFT are applied in synergy to examine drug-target interactions.

Hybrid QM/MM approach accurately elucidates catalytic/inhibitory reaction mechanisms.

The rapidly evolving Coronavirus 2019 (COVID-19) pandemic has led to millions of deaths around the world, highlighting the pressing need to develop effective antiviral pharmaceuticals. Recent efforts with computer-aided rational drug discovery have allowed detailed examination of drug–macromolecule interactions primarily by molecular mechanics (MM) techniques. Less widely applied in COVID-19 drug modeling is density functional theory (DFT), a quantum mechanics (QM) method that enables electronic structure calculations and elucidations of reaction mechanisms. Here, we review recent advances in applying DFT in molecular modeling studies of COVID-19 pharmaceuticals. We start by providing an overview of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs and targets, followed by a brief introduction to DFT. We then provide a discussion of different approaches by which DFT has been applied. Finally, we discuss essential factors to consider when incorporating DFT in future drug modeling research.

COVID-19

SARS-CoV-2

quantum mechanics

density functional theory

rational drug design

molecular modeling

© 2021 Elsevier Ltd. All rights reserved.