title: Computational design of apolipoprotein E4 inhibitors for Alzheimer's disease therapy from traditional Chinese medicine.
abstract: Apolipoprotein E4 (Apo E4) is the major genetic risk factor in the causation of Alzheimer's disease (AD). In this study we utilize virtual screening of the world's largest traditional Chinese medicine (TCM) database and investigate potential compounds for the inhibition of ApoE4. We present the top three TCM candidates: Solapalmitine, Isodesacetyluvaricin, and Budmunchiamine L5 for further investigation. Dynamics analysis and molecular dynamics (MD) simulation were used to simulate protein-ligand complexes for observing the interactions and protein variations. Budmunchiamine L5 did not have the highest score from virtual screening; however, the dynamics pose is similar to the initial docking pose after MD simulation. Trajectory analysis reveals that Budmunchiamine L5 was stable over all simulation times. The migration distance of Budmunchiamine L5 illustrates that docked ligands are not variable from the initial docked site. Interestingly, Arg158 was observed to form H-bonds with Budmunchiamine L5 in the docking pose and MD snapshot, which indicates that the TCM compounds could stably bind to ApoE4. Our results show that Budmunchiamine L5 has good absorption, blood brain barrier (BBB) penetration, and less toxicity according to absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction and could, therefore, be safely used for developing novel ApoE4 inhibitors.
authors: Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors: Hung-Jin
authors: HJ
authors: Huang
authors: Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan.
authors: Hsin-Yi
authors: HY
authors: Chen
authors: School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan.
authors: Cheng-Chun
authors: CC
authors: Lee
authors: Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan ; School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan.
authors: Calvin Yu-Chian
authors: 0000-0003-3306-250X
authors: CY
authors: Chen
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053327:Apolipoprotein E4 / Q000037:antagonists & inhibitors / Q000737:chemistry; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D008516:Medicine, Chinese Traditional; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation
chemical_list: D053327:Apolipoprotein E4