Abstract

Monte Carlo method has been used as a computational tool for building QSAR models for the reactivation of sarin inhibited acetylcholinesterase (AChE) by quaternary pyridinium oximes. Simplified molecular input line entry system (SMILES) together with hydrogen-suppressed graph (HSG) was used to represent molecular structure. Total number of considered oximes was 46 and activity was defined as logarithm of the AChE reactivation percentage by oximes with concentration of 0.001 M. One-variable models have been calculated with CORAL software for one data split into training, calibration and test set. Computational experiments indicated that this approach can satisfactorily predict the desired endpoint. Best QSAR model had the following statistical parameters: for training set r² = 0.7096, s = 0.177, MAE = 0.148; calibration set: r² = 0.6759, s = 0.330, MAE = 0.271 and test set: r² = 0.8620, s = 0.182, MAE = 0.150. Structural indicators (SMILES based molecular fragments) for the increase and the decrease of the stated activity are defined. Using defined structural alerts computer aided design of new oxime derivatives with desired activity is presented.

Keywords: AChE reactivator, Chemoinformatics, CORAL, Drug design, oximes, QSAR, SMILES.