Structure-based discovery and bio-evaluation of a cyclopenta[4,5]thieno[2,3-]pyrimidin-4-one as a phosphodiesterase 10A inhibitor.

Phosphodiesterase10A (PDE10A) is a potential therapeutic target for the treatment of several neurodegenerative disorders. Thus, extensive efforts of medicinal chemists have been directed toward developing potent PDE10A inhibitors with minimal side effects. However, PDE10A inhibitors are not approved as a treatment for neurodegenerative disorders, possibly due to the lack of research in this area. Therefore, the discovery of novel and diverse scaffolds targeting PDE10A is required. In this study, we described the identification of a new PDE10A inhibitor by structure-based virtual screening combining pharmacophore modelling, molecular docking, molecular dynamics simulations, and biological evaluation. Zinc42657360 with a cyclopenta[4,5]thieno[2,3-]pyrimidin-4-one scaffold from the zinc database exhibited a significant inhibitory activity of 1.60 μM against PDE10A. The modelling studies demonstrated that Zinc42657360 is involved in three hydrogen bonds with ASN226, THR187 and ASP228, and two aromatic interactions with TYR78 and PHE283, besides the common interactions with the P-clamp residues PHE283 and ILE246. The novel scaffold of Zinc42657360 can be used for the rational design of PDE10A inhibitors with improved affinity.