DE-NOVO DRUG DESIGN OF NOVEL 1,2,3–TRIAZOLE-NAPHTHAMIDE AS AN INHIBITOR OF SARS-COV-2 MAIN PROTEASE: SYNTHESIS, BIOINFORMATICS AND BIOPHYSICAL STUDIES

Abstract

De novo drug design tends to discover a new chemical entity that sits at the active site of the target protein, receptor or enzyme. It starts by exploiting an existing moiety and we keep modifying it by adding or subtracting fragments step-by-step, so that maybe when a particular group is added it increases the electrostatic interaction or it improves the hydrophobic interaction or it produces a good hydrogen bond donor or it reduces steric repulsions or van der Walls repulsion. Assembling of the novel moieties from pieces that are positioned optimally in favourable regions of the active site a newly designed drug candidate is obtained. Keeping in mind about the havoc caused by SARS, MERS and SARS-CoV-2 we designed a novel triazole molecule triazole-naphthamide with the help of De novo drug design and synthesized it. Indirect medicinal properties were determined by In-Silico approach, ADMET prediction and by steady state fluorescence measurements at 298 K to determine the interaction properties with the transport proteins bovine serum albumin (BSA), human serum albumin (HSA) and Bromelain (BMLN). Complexation for both protein-ligand complexes causes quenching of the tryptophan (Trp) emission presents in the proteins and in the enzymeas evidenced by the fluorescence spectra. This study demonstrates significant binding of this compound to both serum albumins and bromelain. The fluorescence study aids in understanding how the protein's microenvironment deforms in response to ligand interaction. The fluorescence spectroscopic study of Trp residue in protein-ligand complexes showed that the strong quenching with the blue shift of the emission peak of serum albumin proteins whereas quenching of Trp residue of bromelain was associated with a small red shift, all three occurs through static quenching mechanism. Present study of triazole-naphthamide reveals its drug-able nature due to its ability to bind with the serum albumins also indicating its possibility of oral administration since it could bind with bromelain. Binding constant values are evaluated using methods such as Stern-Volmer and modified Scatchard equations.