Consensus Superiority of the Pharmacophore-based Alignment, Over Maximum Common Substructure (MCS): 3D-QSAR Studies on Carbamates as Acetylcholinesterase Inhibitors

Abstract

In view of the nonavailability of complete X-ray structure of carbamates co-crystallized with AChE enzyme, the 3D-QSAR model development based on co-crystallized conformer (CCBA) as well as docked conformer-based alignment (DCBA) is not feasible. Therefore, the only two alternatives viz. pharmacophore and maximum common substructure-based alignments are left for the 3D-QSAR comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analyses (CoMSIA) model development. So, in the present study, the 3D-QSAR models have been developed using both alignment methods, where CoMFA and CoMSIA models based on pharmacophore-based alignment were in good agreement with each others and demonstrated significant superiority over MCS-based alignment in terms of leave-one-out (LOO) cross-validated q2 values of 0.573 and 0.723 and the r2 values of 0.972 and 0.950, respectively. The validation of the best CoMFA and CoMSIA models based on pharmacophore (Hip-Hop)-based alignment on a test set of 17 compounds provided significant predictive r2 [r2pred(test)] of 0.614 and 0.788 respectively. The contour map analyses revealed the relative importance of steric, electrostatic and hydrophobicity for AChE inhibition activity. However, hydrophobic factor plays major contribution to the AChE inhibitory activity modulation which is in strong agreement with the fact that the AChE is having a wide active site gorge (~20Å) occupied by a large number of hydrophobic amino acid residues.