title: Reactivity versus steric effects in fluorinated ketones as esterase inhibitors: a quantum mechanical and molecular dynamics study.
abstract: Carboxylesterases (CEs) are a family of ubiquitous enzymes with broad substrate specificity, and their inhibition may have important implications in pharmaceutical and agrochemical fields. One of the most potent inhibitors both for mammalian and insect CEs are trifluoromethyl ketones (TFMKs), but the mechanism of action of these chemicals is not completely understood. This study examines the balance between reactivity versus steric effects in modulating the activity against human carboxylesterase 1. The intrinsic reactivity of the ketone moiety is determined from quantum mechanical computations, which combine gas phase B3LYP calculations with hydration free energies estimated with the IEF/MST model. In addition, docking and molecular dynamics simulations are used to explore the binding mode of the inhibitors along the deep gorge that delineates the binding site. The results point out that the activity largely depends on the nature of the fluorinated ketone, since the activity is modulated by the balance between the intrinsic electrophilicity of the carbonyl carbon atom and the ratio between keto and hydrate forms. However, the results also suggest that the correct alignment of the alkyl chain in the binding site can exert a large influence on the inhibitory activity, as this effect seems to override the intrinsic reactivity features of the fluorinated ketone. Overall, the results sustain a subtle balance between reactivity and steric effects in modulating the inhibitory activity of TFMK inhibitors.
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, IQAC (CSIC), Jordi Girona 18-26, 08034, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Rayo
authors.forename: Lourdes
authors.initials: L
authors.lastname: Muñoz
authors.forename: Gloria
authors.initials: G
authors.lastname: Rosell
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Angel
authors.initials: A
authors.lastname: Guerrero
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.forename: Ramon
authors.initials: R
authors.lastname: Pouplana
mesh_terms: D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004950:Esterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054879:Halogenation / Q000187:drug effects*; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D007659:Ketones; D004950:Esterases; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human