Consensus superiority of the pharmacophore-based alignment, over maximum common substructure (MCS): 3D-QSAR studies on carbamates as acetylcholinesterase inhibitors.
In view of the nonavailability of complete X-ray structure of carbamates cocrystallized with AChE enzyme, the 3D-QSAR model development based on cocrystallized 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 other and demonstrated significant superiority over MCS-based alignment in terms of leave-one-out (LOO) cross-validated q(2) values of 0.573 and 0.723 and the r(2) 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 r(2) [r(2)(pred(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 a 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 (approximately 20 A) occupied by a large number of hydrophobic amino acid residues.
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, India 226001.
Shailendra S
SS
Chaudhaery
Kuldeep K
KK
Roy
Anil K
AK
Saxena
D000110:Acetylcholinesterase / Q000378:metabolism*; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase