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Organophosphorus compound esterase profiles as predictors of therapeutic and toxic effects.
- Source :
-
Chemico-biological interactions [Chem Biol Interact] 2013 Mar 25; Vol. 203 (1), pp. 231-7. Date of Electronic Publication: 2012 Nov 02. - Publication Year :
- 2013
-
Abstract
- Certain organophosphorus compounds (OPCs) inhibit various serine esterases (EOHs) via phosphorylation of their active site serines. We focused on 4 EOHs of particular toxicological interest: 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 relative degree of inhibition of these EOHs constitutes the "esterase profile" of an OPC and serves as a major determinant of its net physiological effects. Thus, understanding and controlling the esterase profile of OPC activity and selectivity toward these 4 target enzymes is a significant undertaking. In the present study, we analyzed the inhibitor properties of 52 OPCs against the 4 EOHs, along with pairwise and multitarget selectivities between them, using 2 QSAR approaches: Hansch modeling and Molecular Field Topology Analysis (MFTA). The general formula of the OPCs was (RO)(2)P(O)X, where R = alkyl, X = - SCH(Hal)COOEt (Hal = Cl, Br), -SCHCl(2), -SCH(2)Br, -OCH(CF(3))R(1) (R(1) = C(6)H(5), CF(3), COOEt, COOMe). The Hansch model showed that increasing neuropathic potential correlated with rising R hydrophobicity; moreover, OPC binding to scavenger EOHs (BChE and CaE) had different effects on potential acute and delayed neurotoxicity. Predicted protective roles of BChE and CaE against acute toxicity were enhanced with increasing hydrophobicity, but projected 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 CaE without untoward side effects.<br /> (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Acetylcholinesterase metabolism
Animals
Butyrylcholinesterase metabolism
Cholinesterase Inhibitors chemistry
Cholinesterase Inhibitors pharmacology
Cholinesterase Inhibitors toxicity
Drug Design
Drug Evaluation, Preclinical
Enzyme Inhibitors chemistry
Enzyme Inhibitors toxicity
Humans
Hydrophobic and Hydrophilic Interactions
Kinetics
Models, Chemical
Organophosphorus Compounds chemistry
Organophosphorus Compounds toxicity
Quantitative Structure-Activity Relationship
Enzyme Inhibitors pharmacology
Esterases antagonists & inhibitors
Organophosphorus Compounds pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7786
- Volume :
- 203
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Chemico-biological interactions
- Publication Type :
- Academic Journal
- Accession number :
- 23123251
- Full Text :
- https://doi.org/10.1016/j.cbi.2012.10.012