Date Published: January 25, 2017
Publisher: Public Library of Science
Author(s): Salete J. Baptista, Maria M. C. Silva, Elisabetta Moroni, Massimiliano Meli, Giorgio Colombo, Teresa C. P. Dinis, Jorge A. R. Salvador, Alessio Lodola.
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.
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 .
A dynamic structure-based pharmacophore strategy was used to identify novel PARP-1 inhibitors. The pharmacophore models based on the interactions between the PARP-1 catalytic domain and four different inhibitors during MD simulations provided new insights in the ligand binding mode, taking into account the flexibility of both the enzyme and the ligand. Subsequently, the validated pharmacophore models were screened against two virtual compound libraries, to retrieve hits with novel chemical scaffolds. After molecular docking studies using Glide, the top scored drug-like molecules were tested against the PARP kit assay to determine PARP-1 inhibitory activity. Structurally diverse hits with important PARP-1 inhibitory activity were found. Moreover, the dynamic structure-based pharmacophore approach applied here led to the identification of three new PARP-1 inhibitor candidates with skeletons that had not been reported previously: NSC86342, NSC131753, and NSC121848. These candidates will be useful for guiding the further development of novel and more potent PARP-1 inhibitors.