Insights into the selective mechanism of PDE2/9a inhibitors from silico aspects

Abstract

The selective design of competitive enzyme inhibitors is an extremely difficult task but necessary work for certain types of systems, such as the phosphodiesterase (PDE) system addressed in this article. In the PDE family, PDE2A and PDE9 respectively target the central nervous system and heart failure, and share many conserved amino acids at their binding sites. Therefore, gaining a deep understanding of the selective mechanisms of PDE2A/9A is crucial for designing highly selective drugs. In this study, various computer-aided drug design (CADD) methods, including molecular docking, molecular dynamics simulations (MD), and binding free energy calculations, are employed to explore the selective mechanisms of PDE2A/9A. Overall, our research results indicate a selective design strategy for PDE2A, which involves incorporating hydrophobic or aromatic moieties into the molecular structure to better accommodate the hydrophobic pocket of PDE2A. Additionally, it is recommended to introduce functional groups capable of forming connections with selective residues, such as Phe830 and Gln812 for PDE2A, or Ala452 and Tyr424 for PDE9A, to enhance the selectivity of inhibitors targeting PDE2A/9A. This achievement is anticipated to pave the way for the development of innovative and selective small molecules targeting PDE2A/9A.

Communicated by Ramaswamy H. Sarma

Keywords:

• PDE2A
• PDE9A
• selective mechanism
• molecular docking
• molecular dynamics simulation

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The research was financially supported by the Scientific Research Fund of Liaoning Provincial Education Department [2022-MS-247], the Career Development Support Program for Young and Middle-aged Teachers at Shenyang Pharmaceutical University [ZQN2021001], the General Project of Liaoning province Education Department [JYTMS20231359], the Overseas Expertise Introduction Project for Discipline Innovation [Grant No. D20029], and the Scientific Research Fund of Liaoning Provincial Education Department [2020LJC05, 2012520005].