title: 2D QSAR Study for Gemfibrozil Glucuronide as the Mechanism-based Inhibitor of CYP2C8.
abstract: Mechanism-based inhibition of cytochrome P450 involves the bioactivation of the drug to a reactive metabolite, which leads to cytochrome inhibition via various mechanisms. This is generally seen in the Phase I of drug metabolism. However, gemfibrozil (hypolipidemic drug) leads to mechanism-based inhibition after generating glucuronide conjugate (gemfibrozil acyl-β-glucuronide) in the Phase II metabolism reaction. The mechanism involves the covalent binding of the benzyl radical (generated from the oxidation of aromatic methyl group in conjugate) to the heme of CYP2C8. This article deals with the development of a 2D QSAR model based on the inhibitory potential of gemfibrozil, its analogues and corresponding glucuronide conjugates in inhibiting the CYP2C8-catalysed amodiaquine N-deethylation. The 2D QSAR model was developed using multiple linear regression analysis in Accelrys Discovery Studio 2.5 and helps in identifying the descriptors, which are actually contributing to the inhibitory potency of the molecules studied. The built model was further validated using leave one out method. The best quantitative structure activity relationship model was selected having a correlation coefficient (r) of 0.814 and cross-validated correlation coefficient (q(2)) of 0.799. 2D QSAR revealed the importance of volume descriptor (Mor15v), shape descriptor (SP09) and 3D matrix-based descriptor (SpMax_RG) in defining the activity for this series of molecules. It was observed that volume and 3D matrix-based descriptors were crucial in imparting higher potency to gemfibrozil glucuronide conjugate, as compared with other molecules. The results obtained from the present study may be useful in predicting the inhibitory potential (IC50 for CYP2C8 inhibition) of the glucuronide conjugates of new molecules and compare with the standard gemfibrozil acyl-β-glucuronide (in terms of pIC50 values) in early stages of drug discovery and development.
authors.affiliation: Current Address: Amity Institute of Pharmacy, Amity University Campus, A-Block, Ground Floor, Sector-12, Noida-201 303, India.
authors.forename: N
authors.initials: N
authors.lastname: Taxak
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Mohali-160 062, India.
authors.forename: P V
authors.initials: PV
authors.lastname: Bharatam
keywords: 2D descriptors; CYP2C8; Gemfibrozil; QSAR; glucuronide conjugation; mechanism-based inhibition