title: Capture hydrolysis signals in the microsomal stability assay: molecular mechanisms of the alkyl ester drug and prodrug metabolism.
abstract: The hydrolysis of carboxylic acid esters is often catalyzed by carboxylesterases in human liver microsomes, which is also a common 'noise' in the microsomal stability assay, a widely used screening protocol in drug discovery to monitor the activity of cytochrome P450 enzymes. Herein, we captured this 'noise', the hydrolysis signal of small alkyl ester drugs and prodrugs with a unique pairwise analysis of Pfizer's microsomal clearance database. The hydrolysis mechanisms were further elucidated with density functional theory and molecular docking approaches. The results suggested that the electronic properties of ester moieties, tetrahedral intermediate formation energies, and specific drug-enzyme molecular interactions are key factors for the determination of the metabolic fate of the studied alkyl esters, but individually these factors failed to correlate with the observed rate of hydrolysis.
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut 06340, United States. hao.sun@pfizer.com
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
mesh_terms: D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004952:Esters / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008861:Microsomes / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D011789:Quantum Theory; D015398:Signal Transduction
chemical_list: D002264:Carboxylic Acids; D004952:Esters; D011355:Prodrugs; D003577:Cytochrome P-450 Enzyme System