title: Novel PARP-1 Inhibitor Scaffolds Disclosed by a Dynamic Structure-Based Pharmacophore Approach.
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.
authors.affiliation: Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.|Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Salete J
authors.initials: SJ
authors.lastname: Baptista
authors.affiliation: Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.|Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Maria M C
authors.initials: MM
authors.lastname: Silva
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Moroni
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Meli
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
authors.forename: Teresa C P
authors.initials: TC
authors.lastname: Dinis
authors.affiliation: Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.|Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Jorge A R
authors.initials: JA
authors.lastname: Salvador
mesh_terms: D020134:Catalytic Domain; D062313:Databases, Pharmaceutical; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D000071137:Poly (ADP-Ribose) Polymerase-1