Novel PARP-1 Inhibitor Scaffolds Disclosed by a Dynamic Structure-Based Pharmacophore Approach

PARP-1 inhibition has been studied over the last decades for the
treatment of various diseases. Despite the fact that several molecules
act as PARP-1 inhibitors, a reduced number of compounds are used in
clinical practice. To identify new compounds with a discriminatory
PARP-1 inhibitory function, explicit-solvent molecular dynamics
simulations using different inhibitors bound to the PARP-1 catalytic
domain were performed. The representative structures obtained were used
to generate structure-based pharmacophores, taking into account the
dynamic features of receptor-ligand interactions. Thereafter, a virtual
screening of compound databases using the pharmacophore models obtained
was performed and the hits retrieved were subjected to molecular
docking-based scoring. The drug-like molecules featuring the best
ranking were evaluated for their PARP-1 inhibitory activity and IC50
values were calculated for the top scoring docked compounds. Altogether,
three new PARP-1 inhibitor chemotypes were identified.