Reactivity versus steric effects in fluorinated ketones as esterase inhibitors: a quantum mechanical and molecular dynamics study

Josep Rayo (1, 2) , Lourdes Muñoz (1) , Gloria Rosell (3) , Bruce D. Hammock (4) , Angel Guerrero (1) , F. Javier Luque (5) , Ramon Pouplana (5)

1 Department of Biological Chemistry and Molecular Modeling
2 Department of Chemistry
3 Pharmaceutical Chemistry, Unity Associated to CSIC, Faculty of Pharmacy
4 Department of Entomology and Cancer Center
5 Department of Physical Chemistry and Institute of Biomedicine (IBUB), Faculty of Pharmacy

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.

Mots clés: Fluorinated ketones; Esterase; Quantum mechanical computations; Molecular dynamics; Structure-based drug design

Josep Rayo, Lourdes Muñoz, Gloria Rosell, Bruce D. Hammock, Angel Guerrero, et al.. Reactivity versus steric effects in fluorinated ketones as esterase inhibitors: a quantum mechanical and molecular dynamics study. Journal of Molecular Modeling, 2010, 16 (11), pp.1753-1764. ⟨10.1007/s00894-010-0807-4⟩. ⟨hal-00612790⟩