Designing of 2,3-dihydrobenzofuran derivatives as inhibitors of PDE1B using pharmacophore screening, ensemble docking and molecular dynamics approach

Abstract

In recent years, the PDE1B enzyme has become a desirable drug target for the treatment of psychological and neurological disorders, particularly schizophrenia disorder, due to the expression of PDE1B in brain regions involved in volitional behaviour, learning and memory. Although several inhibitors of PDE1 have been identified using different methods, none of these inhibitors has reached the market yet. Thus, searching for novel PDE1B inhibitors is considered a major scientific challenge. In this study, pharmacophore-based screening, ensemble docking and molecular dynamics simulations have been performed to identify a lead inhibitor of PDE1B with a new chemical scaffold. Five PDE1B crystal structures have been utilised in the docking study to improve the possibility of identifying an active compound compared to the use of a single crystal structure. Finally, the structure-activity- relationship was studied, and the structure of the lead molecule was modified to design novel inhibitors with a high affinity for PDE1B. As a result, two novel compounds have been designed that exhibited a higher affinity to PDE1B compared to the lead compound and the other designed compounds.