Abstract
Glucuronidation is often recognized as one of the rate-determining factors that limit the bioavailability of flavonols. Hence, design and synthesis of more bioavailable flavonol(s) would benefit from the establishment of predictive models of glucuronidation using kinetic parameters (e.g., Km, Vmax, CLint=Vmax/Km) derived for flavonols. This paper aims to construct position (3-OH) specific CoMFA models to describe UGT1A9-mediated glucuronidation of flavonols, which can be used to design poor UGT1A9 substrates. The kinetics of recombinant UGT1A9-mediated 3-O-glucuronidation of 30 flavonols was characterized and kinetic parameters (Km, Vmax, CLint) were obtained. The observed Km, Vmax and CLint values of 3-O-glucuornidation ranged 0.04~0.68 μM, 0.04~12.95 nmol/mg/min and 0.06~109.60 ml/mg/min, respectively. To model the UGT1A9-mediated glucuronidation, 30 flavonols were splitted into the training (23 compounds) and test (7 compounds) sets. These flavonols were then aligned by mapping the flavonols to a specific common feature pharmacophore, which were used to construct CoMFA models of Vmax and CLint, respectively. The derived CoMFA models possessed good internal and external consistency and showed statistical significance and substantive predictive abilities (Vmax model: q2 = 0.738, r2= 0.976, r2pred = 0.735; CLint model: q2 = 0.561, r2= 0.938, r2pred = 0.630). The contour maps derived from CoMFA modeling clearly indicated structural characteristics associated with rapid or slow 3-O-glucuronidation. In conclusion, the approach of coupling CoMFA analysis with a pharmacophore-based structural alignment is viable for constructing a predictive model for regiospecific glucuronidation rates of flavonols by UGT1A9.
- Received September 23, 2010.
- Revision received November 3, 2010.
- Accepted November 4, 2010.
- The American Society for Pharmacology and Experimental Therapeutics