Program

P.25 -- Poster, IWTCP-3

Date: Wednesday, 29 July 2015

Time: 08h30 - 10h00

Identification of Potential Drugs for Alzheimer’s Disease by in Silico and in Vitro Experiments

Nguyen Quoc Thai (1,2), Ning-Hsuan Tseng (3), and Yun-Ru Chen (3), and Mai Suan Li (1,4)

(1) Institute for Computational Sciences and Technology, Ho Chi Minh City, Vietnam; (2) Dong Thap University, Dong Thap, Vietnam; (3) Genomics Research Center, Academia Sinica, 128, Academia Rd., Sec. 2, Nankang Dist., Taipei 115, Taiwan; (4) Institute of Physics, Polish Academy of Sciences, Warsaw, Poland

Alzheimer's disease (AD) is a disease of the brain that causes problems with memory, thinking and behavior and effects about 18 million people worldwide in the elderly. Currently, there is no efficient treatment for AD as its origin remains unknown. There exist several hypotheses for AD but the amyloid cascade hypothesis, which posits that AD is caused by oligomerization of Aβ peptides, is widely accepted. Thus the target for our drug design problem is Aβ fibrils (PDB ID: 2LMN). The Lipinski rule and docking method were used as a virtual screening tool to find out top hits from the large data base CHEMSPIDER which contains more than 300000 compounds. Thirty-six top-leads that can easily cross the blood–brain barrier as well as be well absorbed by human body were selected for further study by the more precise steered molecular dynamics (SMD) method. The main idea of this method is that instead of the binding free energy the rupture force needed to unbind a ligand from a receptor is used as a measure of binding affinity, i.e. the higher is rupture force, the stronger is binding. Note that the rupture force is defined as a maximum in the force-time/displacement profile. Using SMD method we have found ten top hits that are recommended for further in vitro experiments. We succeeded to purchase two compounds Hoechst 34580 (C27H29N7) and Hoechst 33342 (C27H28N6O) which are commercially available cell-permeable fluorescent dye for staining DNA and nuclei. Using the AFM and ThT fluorescence we have demonstrated that these two compounds can block Aβ aggregation with the inhibition constant IC50 of about 0.6 and 0.8 µM for Hoechst 34580 and Hoechst 33342, respectively. This experimental result is in qualitative agreement with our estimation of the binding free energy (ΔGbind ≈ -10 kcal/mol) using the MM-PBSA method.

Presenter: Nguyen Quoc Thai