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Title: Novel PARP-1 Inhibitor Scaffolds Disclosed by a Dynamic Structure-Based Pharmacophore Approach
Authors: Baptista, Salete J. 
Silva, Maria M. C. 
Moroni, Elisabetta
Meli, Massimiliano
Colombo, Giorgio 
Dinis, Teresa C. P. 
Salvador, Jorge A. R. 
Issue Date: 2017
Project: Universidade de Coimbra 
SFRH/ BD/80975/2011 
AIRC through project IG 15420 
REEQ/481/QUI/ 2006 
CENTRO-07- CT62-FEDER-002012 
Serial title, monograph or event: PLoS ONE
Volume: 12
Issue: 1
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.
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0170846
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
FFUC- Artigos em Revistas Internacionais

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