Modelling the multi-target selectivity: o-phosphorylated oximes as serine hydrolase inhibitors

Abstract

Understanding, predicting and control of multi-targetselectivity of bioactive compounds is an interesting prob-lem of chemoinformatics. An important example is pre-sented by the organophosphorus compounds that caninhibit at least four major serine hydrolase targets: acetyl-cholinesterase (AChE), butyrylcholinesterase (BChE), car-boxylesterase (CaE) and neuropathy target esterase (NTE).The 'esterase profile' of a compound critically affects itspossible application as pesticide or therapeutic agent aswell as the ecotoxicity risks related to both acute anddelayed toxicity in humans and warm-blooded animals.In this paper, we present the results of the QSAR andmolecular modelling analysis of inhibitory activity andselectivity with respect to AChE, BChE, CaE and NTE for alarge series of O-phosphorylated oximes containing thephosphate, thiophosphate, methylphosphonate and phe-nylphosphonate groups [1]. The compounds of this classare studied as promising agrochemicals and the potentialproducts of reactivation of phosphorylated cholineste-rases by oximes. Using the Molecular Field TopologyAnalysis (MFTA) approach, [2] predictive models andactivity maps for the influence of local (atomic) propertieson the inhibitory activity and selectivity were obtained.The 3D QSAR models based on the Comparative Molecu-lar Field Analysis (CoMFA) technique [3] were alsoderived. These models are mutually consistent, and theirinterpretation is in good agreement [1] with known qual-itative structure-activity relationships as well as the activesite structures of these serine hydrolases identified fromthe X-ray and molecular modelling data.