Ligand-based 3D-QSAR studies of physostigmine analogues as acetylcholinesterase inhibitors

Natural alkaloid Physostigmine is one of the most potent pseudo-irreversible inhibitor of Acetylcholinesterase. It was found to accelerate long-term memory process, but due to its short half life and variable bioavailability, has inconsistent clinical efficacy. 3D-QSAR studies based on the comparative molecular field analysis and comparative molecular similarity indices analysis were applied to a set of 40 Physostigmine derivatives which are divided into two classes: A and B. The study was conducted to obtain a highly reliable and extensive dynamic QSAR model based on alignment procedure with co-crystallized Ganstigmine as template. The strategy yielded significant 3D-QSAR models with the cross-validated q(2) values 0.762 and 0.754 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Resulted models were validated by external set of eight compounds yielding high correlation coefficient r(2) values of 0.730 and 0.720 for comparative molecular field analysis and comparative molecular similarity indices analysis, respectively. Furthermore, the analysis of comparative molecular field analysis and comparative molecular similarity indices analysis contour maps within the active site of AChE were conducted in order to understand the interactions between the receptor and the Physostigmine derivatives. This study will facilitate the rational design of more potent Physostigmine compounds which might have better activity and reduce toxicity for the treatment of Alzheimer disease.