Abstract
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.
Highlights
Poly(ADP-ribose) polymerases (PARPs) comprise a group of enzymes that share the ability to catalyze the attachment of ADP-ribose moieties to specific acceptor proteins and transcription factors, using nicotine adenine dinucleotide (NAD+) as a substrate [1].PARP-1 is the best characterized isoform among the PARP family members and is responsible for 85%-90% of poly(ADP-ribosylation) activity [2]
molecular dynamics (MD) simulations with different known small-molecule inhibitors were carried out to characterize the dynamic features of active site-ligand interactions in the PARP-1 catalytic domain
Those conserved binding interactions were used to develop dynamic pharmacophore models aimed at expanding the chemical diversity space of PARP-1 inhibitors
Summary
Poly(ADP-ribose) polymerases (PARPs) comprise a group of enzymes that share the ability to catalyze the attachment of ADP-ribose moieties to specific acceptor proteins and transcription factors, using nicotine adenine dinucleotide (NAD+) as a substrate [1].PARP-1 is the best characterized isoform among the PARP family members and is responsible for 85%-90% of poly(ADP-ribosylation) activity [2]. The participation of PARP-1 in DNA repair granted it the designation of guardian angel of DNA [7] This nuclear enzyme recognizes and binds to DNA strand-breaks via an N-terminal region, which promotes a conformational change in the C-terminal catalytic domain. As a result, this domain becomes activated, exposing the activation site to NAD+ and leading to the poly(ADP-ribosylation) of many targets, including histones and PARP-1 itself [3, 8]
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