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Esterase profile of organophosphorus compounds (OPC) in prediction of their therapeutic and toxic effectsтезисы доклада
- Авторы: Makhaeva G.F., Radchenko E.V., Palyulin V.A., Rudakova E.V., Aksinenko A.Y., Sokolov V.B., Zefirov N.S., Richardson R.J.
- Сборник: Proceedings of 11th International Meeting on Cholinesterases
- Тезисы
- Год издания: 2012
- Издательство: Kazanskii Gosudarstvennyi Universitet/Kazan State University
- Местоположение издательства: Russian Federation
- Первая страница: 96
- Последняя страница: 96
- Аннотация: OPCs interact with various serine esterases (EOHs) via phosphorylation of serine in their active sites. In particular, these EOHs and effects of their inhibition comprise acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE; inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity, OPIDN). The relationships among these interactions determine the physiological effects of an OPC. Thus, understanding and controlling the ‘esterase profile’ of OPC activity and selectivity toward 4 target enzymes is significant. Inhibitor properties of 52 OPCs of general formula (RO)2P(O)L, where R = Alkyl, L = SCHX(COOEt), -SCHX2 (X = Cl, Br), -OCH(CF3)R1 (R1=CF3, COOEt, C6H5) against AChE, BChE, CaE, and NTE, along with pairwise and multitarget selectivities between them, have been analysed using two QSAR approaches. First, a Hansch model showed that increasing neuropathic potential correlated with rising R hydrophobicity; moreover, OPC binding to scavenger EOH (BChE and CaE) had different effects on acute and delayed neurotoxicity. Protective roles of BChE and CaE against acute toxicity were enhanced with increasing hydrophobicity, but protection against OPIDN was decreased. Next, Molecular Field Topology Analysis (MFTA) models were built, considering atomic descriptors, e.g., effective charge, van der Waals radius of environment, and group lipophilicity. Activity/selectivity maps confirmed predictions from Hansch models and revealed other structural factors affecting activity and selectivity. Virtual screening based on multitarget selectivity MFTA models was used to design libraries of OPCs with favorable esterase profiles for potential application as selective inhibitors of BChE and CaE without untoward side effects.
- Добавил в систему: Радченко Евгений Валерьевич