Chao Yuanyuan, Zhang Lin
Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China.
Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China.
Biophys Chem. 2022 Mar;282:106746. doi: 10.1016/j.bpc.2021.106746. Epub 2021 Dec 22.
Immune checkpoint inhibitors have become a hot spot in the treatment of acute myeloid leukemia (AML), the most common acute leukemia (blood cancer) in adults. In the present study, molecular insights into the molecular interactions between an immune checkpoint leukocyte immunoglobulin-like receptor b4 (LILRB4) and its mAb h128-3 was explored using molecular dynamics (MD) simulation for the biomimetic design of peptide inhibitor of LILRB4. Both hydrophobic interaction and electrostatic interaction were found favorable for the binding of the mAb h128-3 on LILRB4, and hydrophobic interaction was identified as the main driving force. The key amino acid residues for the binding of mAb h128-3 on LILRB4 were identified as Y93, D94, D106, Y34, S103, W107, Y61, N30, E27, Y33, Y59, W95, S92 through MM-PBSA (molecular mechanics-Poisson-Boltzmann surface area) method. Based on this, an inhibitor library with the sequence of SXDXYXSY (Where X is an arbitrary amino acid residue) were designed. Two peptide inhibitors, SADHYHSY and SVDWYHSY were obtained through screening using molecular docking and MD simulations, and then validated by successful blocking of LILRB4 through the covering of LILRB4 surface by these inhibitors. These results would be helpful for the research and development of therapies for AML.
免疫检查点抑制剂已成为治疗急性髓系白血病（AML）的热点，AML是成人中最常见的急性白血病（血癌）。在本研究中，利用分子动力学（MD）模拟探索免疫检查点白细胞免疫球蛋白样受体b4（LILRB4）与其单克隆抗体h128 - 3之间的分子相互作用，以进行LILRB4肽抑制剂的仿生设计。发现疏水相互作用和静电相互作用均有利于单克隆抗体h128 - 3与LILRB4的结合，且疏水相互作用被确定为主要驱动力。通过分子力学 - 泊松 - 玻尔兹曼表面积（MM - PBSA）方法确定单克隆抗体h128 - 3与LILRB4结合的关键氨基酸残基为Y93、D94、D106、Y34、S103、W107、Y61、N30、E27、Y33、Y59、W95、S92。基于此，设计了序列为SXDXYXSY（其中X为任意氨基酸残基）的抑制剂文库。通过分子对接和MD模拟筛选获得了两种肽抑制剂SADHYHSY和SVDWYHSY，然后通过这些抑制剂覆盖LILRB4表面成功阻断LILRB4进行验证。这些结果将有助于AML治疗方法的研发。
