Wu Xingyu, Zhu Xi, Fang Min, Qi Fenghua, Yin Zhixiang, Zhang John Z H, Luo Shihua, Zhu Tong, Gao Ya
School of Mathematics, Physics and Statistics, Shanghai University of Engineering Science, Shanghai 201620, China.
School of Electronic Engineering, Nanjing Xiaozhuang University, Nanjing 211171, China.
Molecules. 2025 Jul 14;30(14):2962. doi: 10.3390/molecules30142962.
The design of small-molecule inhibitors targeting proprotein convertase subtilisin/Kein type 9 (PCSK9) remains a forefront challenge in combating atherosclerosis. While various monoclonal antibodies have achieved clinical success, small-molecule inhibitors are hindered by the unique structural features of the PCSK9 binding interface. In this study, a potential small-molecule inhibitor was identified through virtual screening, followed by molecular dynamics (MD) simulations to explore the binding mechanisms between the inhibitor and the PCSK9 protein. Binding free energies were calculated using molecular mechanics/Generalized Born surface area (MM/GBSA) with the interaction entropy (IE) method, and critical hot-spot residues were identified via alanine scanning analysis. Key residues, including ARG237, ILE369, ARG194 and PHE379, were revealed to form critical interactions with inhibitor and play dominant roles during the inhibitor's binding. In addition, the polarization effect was shown to significantly influence PCSK9-ligand binding. The identified inhibitor exhibited highly similar binding patterns with two known active compounds, providing valuable insights for the rational design and optimization of small-molecule inhibitors targeting PCSK9. This work contributes to the development of more effective treatments for hyperlipidemia and associated cardiovascular diseases.
设计靶向前蛋白转化酶枯草杆菌蛋白酶/克恩型9（PCSK9）的小分子抑制剂仍然是对抗动脉粥样硬化的一项前沿挑战。虽然各种单克隆抗体已取得临床成功，但小分子抑制剂却因PCSK9结合界面独特的结构特征而受到阻碍。在本研究中，通过虚拟筛选鉴定出一种潜在的小分子抑制剂，随后进行分子动力学（MD）模拟以探究该抑制剂与PCSK9蛋白之间的结合机制。使用分子力学/广义玻恩表面积（MM/GBSA）结合相互作用熵（IE）方法计算结合自由能，并通过丙氨酸扫描分析确定关键热点残基。结果显示，包括ARG237、ILE369、ARG194和PHE379在内的关键残基与抑制剂形成关键相互作用，并在抑制剂结合过程中起主导作用。此外，极化效应被证明对PCSK9-配体结合有显著影响。所鉴定的抑制剂与两种已知活性化合物表现出高度相似的结合模式，为合理设计和优化靶向PCSK9的小分子抑制剂提供了有价值的见解。这项工作有助于开发更有效的高脂血症及相关心血管疾病治疗方法。
