Program

P.14 -- Poster, IWTCP-3

Date: Wednesday, 29 July 2015

Time: 08h30 - 10h00

Interactions between small molecules and amyloid beta peptides: Implications for Alzheimer’s disease

Son Tung Ngo (1,2) and Mai Suan Li (2)

(1) Institute for Computational Science and Technology, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam; (2) Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw, Poland

Since available drugs can not cure the Alzheimer’s disease (AD), the computer-aided drug design has become one of the most important tools to search for potential AD drugs recently. According to the amyloid cascade hypothesis, supported by many experiments, the self-assembly of amyloid beta (Aβ) peptides into aggregates is the major cause for this disease. Thus Aβ oligomers and fibrils are target for our computational study. Combining the molecular docking and molecular dynamics simulations to study the binding affinity of ligands to Aβ peptides, we found that small molecules Curcumin (diferulomrthane), Naproxen, Ibuprofen, [1] Propafenone [2], Dracorubin, Taraxerol, Taraxasterol, Hinokiflavone, Diosgenin [3], Vitamin K3 analogues (VK3-6, VK3-8, VK3-9, VK3-10, and VK3-224) [4] are potential compounds that may be inhibit Aβ aggregation. The binding poses of these ligands to receptors were predicted by the docking method while the binding free energy was refined using either the molecular mechanic-Poisson Boltzmann surface area or free energy perturbation methods. The binding mechanism of potential inhibitors was discovered that the interaction between ligand and Aβ is driven by the van der Waals interaction. The change in Aβ structures upon ligand binding have been also considered to clarify the impact of inhibitors on Aβ self-assembly. The pharmacological characteristics of potential drugs including the absorption, distribution, metabolism, excretion, and toxicity were studied using in silico and in vitro experiments. Finally, anti-arrhythmic medication Propafenone [2], Dracorubin, Taraxerol [3], VK3-10, VK3-6, and VK3-9 [4] were found to be more potent than Curcumin in blocking Aβ activity. Our theoretical results have been confirmed by in vitro experiments. References: 1. Son Tung Ngo and M. S. Li, Curcumin binds to Ab40 peptides and fibrils stronger than ibuprofen and naproxen, J.Phys. Chem. B 116, 10165 (2012). 2. Son Tung Ngo, Shang-Ting Fang, Shu-Hsiang Huang, Chao-Liang Chou, Mai Suan Li,Yi-Cheng Chen, Anti-arrhythmic medication Propafenone is potential drug for Alzheimer’s disease by inhibiting aggregation of amyloid beta peptide: in silico and in vitro studies (submitted for publication). 3. P.D.Q. Huy*, Y-C. Yu*, Son Tung Ngo*, Tran Van Thao, C-P Chen, M. S. Li, and Y-C Chen, In silico and in vitro characterization of anti-amyloidogenic activity of vitamin K3 analogues for Alzheimer's disease, BBA-General Subjects 1380, 2960 (2013) (*: contribution equally to the work). 4. Son Tung Ngo and M. S. Li, Top-Leads from natural products for treatment of Alzheimer's disease: Docking and molecular dynamics study, Molecular Simulation 39, 279-291 (2013).

Presenter: Ngo Son Tung