Autor(es):
Baptista, Salete J. ; Silva, Maria M. C. ; Moroni, Elisabetta ; Meli, Massimiliano ; Colombo, Giorgio ; Dinis, Teresa C. P. ; Salvador, Jorge A. R.
Data: 2017
Identificador Persistente: https://hdl.handle.net/10316/108321
Origem: Estudo Geral - Universidade de Coimbra
Projeto/bolsa:
info:eu-repo/grantAgreement/FCT/SFRH/SFRH/PT;
Assunto(s): Catalytic Domain; Databases, Pharmaceutical; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Poly (ADP-Ribose) Polymerase-1; Protein Binding; Structure-Activity Relationship; Models, Molecular
Descrição
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.
JARS thanks Universidade de Coimbra for financial support. SJB thanks Fundação para a Ciência e a Tecnologia for financial support (SFRH/BD/80975/2011). GC acknowledges funding from AIRC through project IG 15420. The authors gratefully acknowledge UC-NMR facility, which is supported by FEDER – European Regional Development Fund through the COMPETE Programme (Operational Programme for Competitiveness), as well as by National Funds through FCT – Fundação para a Ciência e a Tecnologia (Portuguese Foundation for Science and Technology) through grants REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012, CENTRO-07- CT62-FEDER-002012, and Rede Nacional de Ressonância Magnética Nuclear (RNRMN), for NMR data.
