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

• Autor(a) principal: Baptista, Salete J.
• Data de Publicação: 2017
• Outros Autores: Silva, Maria M. C., Moroni, Elisabetta, Meli, Massimiliano, Colombo, Giorgio, Dinis, Teresa C. P., Salvador, Jorge A. R.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/108321; https://doi.org/10.1371/journal.pone.0170846
• topic: Catalytic Domain; Databases, Pharmaceutical; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Poly (ADP-Ribose) Polymerase-1; Protein Binding; Structure-Activity Relationship; Models, Molecular

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.