Locuson Charles W, Wahlstrom Jan L, Rock Denise A, Rock Dan A, Jones Jeffrey P
Washington State University, School of molecular Biosciences, Pullman, WA 99164-4630, USA.
Drug Metab Dispos. 2003 Jul;31(7):967-71. doi: 10.1124/dmd.31.7.967.
Noncovalent forces, other than hydrophobic interactions, are important determinants of substrate bias exhibited by some cytochromes P450. The CYP2C9 pharmacophore is proposed to include either an anionic group or hydrogen bond donor in addition to its hydrophobic groups. By constructing analogs of benzbromarone, evidence supporting the existence of a 2C9 anion-binding site was revealed. A nonsubstituted phenol analog was determined to have a pKa of 8.4 and a Ki of 414 nM whereas those with dihalogenated benzoyl phenols had pKa values between 4.2 to 5.2 and Ki values as low as 1 nM. The nonhalogenated, nonionizable analog is the poorest binder at 796 nM. The Ki range covers around three orders of magnitude with even the weakest binder being a more potent inhibitor than 2C9 substrate phenytoin. Thus, benzbromarone derivatives represent a class of molecules with the potential to reveal more structural details of the 2C9 active site.
除疏水相互作用外，非共价力是一些细胞色素P450表现出底物选择性的重要决定因素。有人提出，CYP2C9药效团除疏水基团外，还包括一个阴离子基团或氢键供体。通过构建苯溴马隆类似物，揭示了支持2C9阴离子结合位点存在的证据。一种未取代的酚类似物的pKa为8.4，Ki为414 nM，而那些带有二卤代苯甲酰酚的类似物的pKa值在4.2至5.2之间，Ki值低至1 nM。未卤代、不可电离的类似物是结合力最差的，其Ki为796 nM。Ki范围涵盖约三个数量级，即使是结合力最弱的类似物也是比2C9底物苯妥英更有效的抑制剂。因此，苯溴马隆衍生物代表了一类有可能揭示2C9活性位点更多结构细节的分子。
