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Serine esterases present important targets in toxicology and therapy. One of the most prominent groups of their inhibitors, organophosphorus compounds (OPC), are valuable drugs for treatment of the Alzheimer’s disease and other disorders. They are also widely used in the industry and may pose safety risks due to their acute and delayed neurotoxicity. The OPC biological effects are determined by their ability to inhibit a number of serine esterases – acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carboxylesterase (CaE), and neuropathy target esterase (NTE) – via irreversible binding through covalent serine modification. Thus, understanding and controlling the ‘esterase profile’ of activity and selectivity towards four key target enzymes is of great interest. In this study, the antiesterase activity and selectivity of 58 O phosphorylated oximes containing the phosphate, thiophosphate, methylphosphonate and phenylphosphonate moieties with different leaving groups were analyzed by means of the Molecular Field Topology Analysis (MFTA), CoMSIA and molecular docking. All three methods provide mostly consistent and mutually complementary information and reveal factors governing the inhibitor activity and selectivity. The esterase inhibitors suitable as novel anti-Alzheimer drugs should have high selectivity to BChE, low activity to AChE, low or no activity to NTE, and possibly moderate activity to CaE. This multi-target / multi-objective optimization problem is difficult to solve based on the consideration of individual activities and selectivities. It is beneficial to introduce integrated parameters of positive and negative effects that are based on domain knowledge and easily interpretable. They can be constructed as generalized mean values of the respective individual activities. In this study, the power-3 (cubic) mean was used as a simple function that increases monotonously with increasing individual values while being partially dominated by larger values. Thus, we introduce the integrated AChE & NTE inhibitor activity parameter as AAN = [ ½ (AA3 + AN3) ]1/3. The main objective parameter for optimization, selectivity to BChE vs AChE & NTE, is then defined as SB|AN = AB – AAN. The virtual screening of potential selective BChE inhibitors in a generated structure library of O phosphorylated oximes yields a focused library of 116 structures having high predicted selectivity and activity to BChE (SB|AN > 3.5, AB > 9). [1] G.F. Makhaeva, E.V. Radchenko, I.I. Baskin, V.A. Palyulin, R.J. Richardson, N.S. Zefirov, SAR QSAR Env. Res., submitted.