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Development of a 3D-QSAR model for acetylcholinesterase inhibitors using a combination of fingerprint, docking, and structure-based pharmacophore approaches - Conference Abstract
Citation:
Lee, S. AND M. Barron. Development of a 3D-QSAR model for acetylcholinesterase inhibitors using a combination of fingerprint, docking, and structure-based pharmacophore approaches - Conference Abstract. Asiatox 2015, Jeju Island, SOUTH KOREA, June 23 - 26, 2015.
Impact/Purpose:
In this study, a 3D QSAR model is developed and tested for AChE inhibitors
Description:
Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in animals, has been used as a target for drugs and pesticides. With the increasing availability of AChE crystal structures, with or without ligands bound, structure-based approaches have been successfully applied for AChE inhibitors. The major limitation observed in these approaches has been the small application domain due to the lack of structural diversity in the training set. In this study, we developed a three dimensional quantitative structure-activity relationship (3D-QSAR) for predicting inhibitory activity of reversible and irreversible AChE inhibitors by combining structure-based pharmacophore and docking studies. To rationalize the structural requirements of inhibitors for interaction with side chains in multiple subsites, docked conformation was overlapped with pharmacophore and transformed into a 3D fingerprint as a descriptor. The modeling approach also included a molecular size filter to address the narrow active site gorge of AChE. The 3D-QSAR model yielded a correlation coefficient of R2 = 0.9, and 80 out of 89 compounds (90%) were predicted within a 1 log unit error. External validation testing on 335 compounds showed high accuracy in discriminating between AChE inhibitors and structural analogs including degradates. The model revealed that the compounds with proper conformation in the active site gorge and the interactions with the crucial amino acid residues, in particular interact with Trp86 and Phe337 at the catalytic anionic site (CAS), Trp286 at peripheral anionic site (PAS), and Gly121, Gly122, and Ala204 at the Oxyanion hole, showed inhibition potencies.