Huang Junhao, Hu Baichun, Xu Ziqi, Ye Yunxia, Wang Huibin, Wang Shuxiang, Liu Zhilong, Wang Jian
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China.
J Mol Model. 2021 Dec 14;28(1):9. doi: 10.1007/s00894-021-04934-7.
Understanding the selectivity mechanism of inhibitors towards homology proteins helps to design selective candidates. Phosphodiesterase (PDE) family members act in the degradation of cAMP and cGMP, among which some isoforms such as PDE9A are attracting interest for Alzheimer's disease treatment, while PDE10A is used as target for treating schizophrenia. In this study, computational methods were used to investigate the major features of PDE9A/10A, with the purpose to provide deep understanding of the molecular mechanism of selective inhibition towards these two isoforms. Our result revealed that two conserved residues Gln453 and Phe456 were proven to be crucial for the binding affinity and inhibitory selectivity of PDE9A inhibitors. In addition, the high-affinity PDE9A inhibitors always interact with the conservative hydrophobic pocket as well as Tyr424 and Ala452 of PDE9A, while PDE10A selective inhibitors need to have two hydrophobic groups and two hydrogen bond donors to interact with the conservative Tyr693, Gln726, and Phe729 of PDE10A. This study provides valuable insights into the underlying mechanism of selective inhibition targeting PDE9A and PDE10A, for further search for potent and highly selective PDE9A/10A inhibitors.
了解抑制剂对同源蛋白的选择性机制有助于设计选择性候选药物。磷酸二酯酶（PDE）家族成员参与cAMP和cGMP的降解，其中一些亚型如PDE9A在阿尔茨海默病治疗中引起了关注，而PDE10A被用作治疗精神分裂症的靶点。在本研究中，采用计算方法研究了PDE9A/10A的主要特征，旨在深入了解对这两种亚型的选择性抑制的分子机制。我们的结果表明，两个保守残基Gln453和Phe456被证明对PDE9A抑制剂的结合亲和力和抑制选择性至关重要。此外，高亲和力的PDE9A抑制剂总是与PDE9A的保守疏水口袋以及Tyr424和Ala452相互作用，而PDE10A选择性抑制剂需要有两个疏水基团和两个氢键供体才能与PDE10A的保守Tyr693、Gln726和Phe729相互作用。本研究为靶向PDE9A和PDE10A的选择性抑制的潜在机制提供了有价值的见解，有助于进一步寻找强效且高选择性的PDE9A/10A抑制剂。
