Quantitative structure-activity relationship (QSAR) analysis of the inhibitory effects of furanocoumarin derivatives on cytochrome P450 3A activities.

Furanocoumarin derivatives (FCs) present in grapefruit and other plants cause pharmacokinetic interactions such as increased absorption of various drugs because the constituents have inhibitory effects on drug metabolizing activities of cytochrome P450 (CYP) 3A that is expressed in intestinal mucosal cells. Though it has been 20 years since such an interaction was discovered, little is still known about the relationship between the molecular characters of FCs and their inhibitory effects. Therefore, the chemical and physicochemical characterizations of the biological activities of FCs were examined by quantitative structure-activity relationship (QSAR) analysis using 37 types of FCs. Common logarithmic IC50 values of human liver microsomal testosterone 6beta-hydroxylations were configured as objective variables. A variety of structural, physicochemical, and quantum chemical descriptors were calculated from 2D and optimized 3D structures in the 37 FCs as explanatory variables. Simple and multiple linear regression analyses were used to evaluate these parameters. Constructed regression models were validated with leave-one-out cross validation and applicable regression diagnostic methods. As a result, logP value, molecular volume, molecular weight, molecular surface area, polar surface area, minimal electrostatic potential, formation energy, and homo energy of each FC were significantly related with the logIC50 value. These relationships indicate that molecular characteristics including lipophilicity, molecular size, electrostatic stabilization, and electron-donating ability of FCs can control FC-CYP interactions. These findings could be useful to predict CYP inhibitory effects of other FCs in foods, drinks, and other natural products such as grapefruit juice and herbal drugs.