Computer simulation to identify selective inhibitor for human phosphodiesterase10A

Abstract

Phosphodiesterases (PDEs) play an important function in transduction of cellular signals by modulating the activation of G-proteins by hydrolyzing cAMP and cGMP. PDE10A has emerged as an inhibitory target for development of effective therapeutics against various disorders such as schizophrenia, psychosis, Huntington disease, and other disorders related to the central nervous system. We utilized various computational methods such as molecular docking, molecular dynamic simulations, and MM-PBSA to find a more potent and selective PDE10A inhibitor compared to papaverine, which is a known standard inhibitor of PDE10A. Molecular docking of papaverine and twenty-eight in house synthesized 3-Methylenisoindolin-1-one based molecules provided two potential lead molecules (molecule #3 and molecule #28), which could be developed as potent PDE10A inhibitors. However, molecule #28 was excluded from further studies due to its cross reactivity with other PDE isoforms. Molecular dynamics and MM-PBSA techniques were used to further analyze the molecular docking results. Molecule #3 binds to the conserved substrate recognizing residue (Gln726) and also fits into the selectivity pocket by anchoring to the hydrophobic residue Tyr693. This study provides a promising candidate molecule that could be developed as a more potent and selective inhibitor of PDE10A.