Ab initio Modeling of Hydrogen Bonding of Remdesivir and Adenosine with Uridine

Abstract

Remdesivir (RDV) emerged as an effective drug against the SARS‐CoV‐2 virus pandemic. One of the crucial steps in the mechanism of action of RDV is its incorporation into the growing RNA strand. RDV, an adenosine analogue, forms Watson‐Crick (WC) type hydrogen bonds with uridine in the complementary strand and the strength of this interaction will control efficacy of RDV. While there is a plethora of structural and energetic information available about WC H‐bonds in natural base pairs, the interaction of RDV with uridine has not been studied yet at the atomic level. In this article, we aim to bridge this gap, to understand RDV and its hydrogen bonding interactions, by employing density functional theory (DFT) at the M06‐2X/cc‐pVDZ level. The interaction energy, QTAIM analysis, NBO and SAPT2 are performed for RDV, adenosine, and their complex with uridine to gain insights into the nature of hydrogen bonding. The computations show that RDV has similar geometry, energetic, molecular orbitals, and aromaticity as adenosine, suggesting that RDV is an effective adenosine analogue. The important geometrical parameters, such as bond distances and red‐shift in the stretching vibrational modes of adenosine, RDV and uridine identify two WC‐type H‐bonds. The relative strength of these two H‐bonds is computed using QTAIM parameters and the computed hydrogen bond energy. Finally, the SAPT2 study is performed at the minima and at non‐equilibrium base pair distances to understand the dominant intermolecular physical force. This study, based on a thorough analysis of a variety of computations, suggests that both adenosine and RDV have similar structure, energetic, and hydrogen bonding behaviour.