Identification of dual site inhibitors of tankyrase through virtual screening of protein-ligand interaction fingerprint (PLIF)–derived pharmacophore models, molecular dynamics, and ADMET studies

Abstract

Tankyrases are the group of poly (ADP-ribosyl) polymerases (PARPs) which are the attractive targets in various therapeutic areas such as cancer, antiviral, diabetes, and hormonal imbalance. The selective nature of tankyrase 1 and 2 inhibitors has created solid base to get dual site binders as they bind to induced adenosine binding site and nicotinamide binding site resulting in dual site inhibition. The present work describes the cheminformatics approach to find potential lead molecules as tankyrases dual site inhibitors through pharmacophore model by utilizing protein-ligand interaction fingerprints (PLIF) approach. The constructed pharmacophore model was used in virtually screening of ZINC and Interbioscreen database. Top ten hit molecules of virtual screening were subjected to molecular docking in order gain insights of key interactions at the adenosine and nicotinamide binding sites. The top hits were subjected to molecular dynamics simulation studies to gain deeper insights into probable mechanism of inhibition and stability of the complex. The top hit ZINC12973507 showed all the features required in key interactions at the active site of tankyrases and this hit molecule can be further explored as a potential drug candidate for dual site inhibition of tankyrases.