Journal of Proteomics & Bioinformatics
Open Access

Computer-aided drug design for Alzheimer’s disease

5^th International Conference on Proteomics & Bioinformatics

September 01-03, 2015 Valencia, Spain

Mai Suan Li

Institute of Physics Polish Academy of Sciences, Poland

Posters-Accepted Abstracts: J Proteomics Bioinform

Abstract :

In the first part of this talk I shall present our new method for finding the optimal path to pull a ligand from the binding pocket by the steered molecular dynamics (SMD). The optimal path corresponds to the minimal hindrance introduced as a scoring function to ligand displacement. Contrary to the existing caver method, our approach takes into account the geometry of ligand leading to much better correlation between experimental inhibition constants and mechanical works estimated by SMD. In the second part the virtual screening, improved SMD and MM-PBSA methods are applied to search for potential drugs for the Alzheimerâ�?�?s disease (AD) from large data bases of natural and synthesized compounds. The design strategy is based on the amyloid cascade hypothesis which posits that AD is caused by aggregation of amyloid beta (A�?²) peptides. Oligomers and protofibrils were taken as drug targets as they seem to be more cytotoxic than mature fibrils. Some of top-hit compounds predicted by our in silico study have already passed in vitro tests for inhibition activity, blood-brain barrier crossing and non-toxicity to cells. Concerning peptide-based inhibitors, we have shown that presence of tryptophan and proline residues in tripeptides is crucial for their tight binding to A�?² fibrils as well as for extensive fibril depolymerization. Fullerenes and their derivatives were found to have high binding affinity to A�?² and ability to block A�?² aggregation. The binding free energy linearly scales with the size of fullerenes.

Biography :

Email: masli@ifpan.edu.pl