Sharif University of Technology, School of Mechanical Engineering, Tehran, Iran.
Sharif University of Technology, School of Mechanical Engineering, Tehran, Iran.
Arch Biochem Biophys. 2018 Sep 1;653:1-9. doi: 10.1016/j.abb.2018.06.004. Epub 2018 Jun 12.
According to the Amyloid hypothesis, as the foremost scientific explanation for Alzheimer Disease (AD), the neuropathology of AD is related to toxic fragments of amyloid beta (Aβ) protein. Based on this hypothesis, an attractive therapeutic approach was demonstrated to identify multifunctional peptides able to modulate Aβ pathologies as the source of AD. On this premise, a bifunctional polypeptide based on the iAβ5p lead compound, was designed to inhibit Aβ aggregation and free metal ions. Herein, the efficacy of this novel drug in Zn and Cd ion chelation was examined through an integrated technique comprising combined Docking, QM, and MD simulations. MD relaxation of a set of probable binding modes that were predicted by Molecular Docking, revealed six druggable hosts having considerable affinities. Further, free energy analysis indicated that the formation of the revealed polypeptide-ion complexes is more spontaneous than the presented Aβ-ion ones. These findings certified the new ability of the modified lead compound to hamper Aβ pathologies and provide helpful information in atomic details for further preclinical studies against AD.
根据淀粉样蛋白假说，作为阿尔茨海默病（AD）的首要科学解释，AD 的神经病理学与毒性淀粉样蛋白 β（Aβ）蛋白片段有关。基于这一假说，一种有吸引力的治疗方法被证明是识别多功能肽，能够调节 Aβ 病理学，作为 AD 的来源。在此前提下，设计了一种基于 iAβ5p 先导化合物的双功能多肽，以抑制 Aβ 聚集和游离金属离子。在此基础上，通过包括对接、QM 和 MD 模拟在内的综合技术，研究了这种新型药物在 Zn 和 Cd 离子螯合方面的功效。通过分子对接预测的一组可能结合模式的 MD 弛豫，揭示了六个具有相当亲和力的可成药宿主。此外，自由能分析表明，揭示的多肽-离子复合物的形成比呈现的 Aβ-离子复合物更自发。这些发现证明了改性先导化合物抑制 Aβ 病理学的新能力，并为进一步的针对 AD 的临床前研究提供了原子细节的有用信息。
