An in-vitro and in-silico approaches in exploring the molecular contact of COVID-19 antiviral drug molnupiravir with human serum albumin: effect of binding on protein structure

Abstract

Protein structure and function are an important aspect in cellular organisms. The function of protein depends on its structural integrity. Changes in its structure may affect to its function leading to disease states. Therefore, understanding the structural integrity of protein both in its free and bound states are very important in medicinal chemistry and biophysical aspects of drug-protein interactions. The COVID-19 antiviral drug molnupiravir (MPV) was used for treatment of COVID-19 illness. The effect of MPV on secondary structure of human serum albumin (HSA) has been investigated from a biophysical perceptive using experimental and docking methods based on binding models. Binding strength of MPV with HSA was 10⁵ M^-1 order. Observed fluorescence quenching of HSA by MPV was static type with quenching constant of 10⁵ M^-1 order. Thermodynamic parameters (ΔG⁰, ∆H⁰, and ∆S⁰) suggested the spontaneity of contact with hydrogen bonding and van der Waals forces are being the primary forces. Binding-induced structural and conformational changes were visible from synchronous fluorescence and circular dichroism (CD) studies. The 3D fluorescence studies further complemented the conformational observations. Molecular docking of MPV with HSA showed its preferred location at site-1 and corroborated the experimental results. 2D diagram and ligplot assisted to analyse the interface residues in docked complex due to binding. The outcome of this study can be useful to decipher the binding behaviour of other drugs and in design of new drugs of better potential besides possible aid in pharmacodynamic studies of similar molecules.

Keywords: Human serum albumin; Molecular docking; Molnupiravir; Secondary structure; Thermodynamic parameters.