Selectivity mechanism of inhibition towards Phosphodiesterase 1B and phosphodiesterase 10A in silico investigation.

Due to the unclear selectivity of the protein system, designing selective small molecule inhibitors has been a significant challenge. This issue is particularly prominent in the phosphodiesterases (PDEs) system. Phosphodiesterase 1B (PDE1B) and phosphodiesterase 10 A (PDE10A) are two closely related subtypes of PDE proteins that play diverse roles in the immune system and tumorigenesis, respectively. Distinguishing the selective mechanism of these two subtypes is crucial for maximizing therapeutic efficacy and minimizing the side effects of inhibitors. We have investigated the interactions between crucial amino acid residues and selective inhibitors through several computer-aided drug design methods such as molecular docking, molecular dynamic simulation, MM/GBSA calculation, and alanine scanning mutagenesis revealing the selective inhibition mechanism between PDE1B and PDE10A. Our finding shows the selective residues of PDE1B are His373 and Gln421, while the selective residues for PDE10A are Tyr683 and Phe719. Specifically, PDE10A inhibitors form hydrogen bonds and hydrophobic interactions with Tyr683 and Phe719, whereas PDE1B inhibitors only demonstrate weak hydrophobic interactions in the corresponding region. Overall, elucidating the selectivity mechanism underlying the differential interaction between PDE1B and PDE10A is crucial for designing inhibitors with distinct selectivity towards PDE1B/10 A.