Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Eur J Med Chem. 2010 Sep;45(9):4354-7. doi: 10.1016/j.ejmech.2010.05.032. Epub 2010 May 20.
AKR1B10, a human member of the aldo-keto reductase (AKR) superfamily, was recently identified to be linked with several types of cancers, while exhibiting high sequence identity with human aldose reductase (AKR1B1). In order to identify potential inhibitors of AKR1B10, the NCI database which contains approximately 250,000 chemical structures was screened using in silico techniques. Computer aided ligand docking was carried out using the automated Glide program, and potential ligands were selected out based on their chemical complementarity and steric fit within the active site of the enzyme. One of the ligands, 9-methyl-2,3,7-trihydroxy-6-fluorone, showed an IC(50) value of 0.4 microM with a 4-fold selectivity towards AKR1B10 relative to AKR1B1, and its inhibition was competitive with respect to the substrate, showing a K(i) value of 0.2 microM. In addition, through molecular docking in both the AKR1B10-NADP(+) and AKR1B1-NADP(+) complexes, as well as site-directed mutagenesis, non-conserved residues which are involved in inhibitor binding to AKR1B10 were identified and included Lys125 and Gln303.
AKR1B10 是醛酮还原酶 (AKR) 超家族的一个人类成员，最近被确定与多种类型的癌症有关，同时与人类醛糖还原酶 (AKR1B1) 具有高度的序列同一性。为了鉴定 AKR1B10 的潜在抑制剂，使用计算机辅助配体对接技术，对包含约 250,000 个化学结构的 NCI 数据库进行了筛选。计算机辅助配体对接使用自动化 Glide 程序进行，根据其在酶活性部位的化学互补性和空间适应性，选择潜在的配体。其中一种配体，9-甲基-2,3,7-三羟基-6-氟酮，对 AKR1B10 的 IC50 值为 0.4μM，相对于 AKR1B1 具有 4 倍的选择性，其抑制作用相对于底物是竞争性的，K(i) 值为 0.2μM。此外，通过在 AKR1B10-NADP(+)和 AKR1B1-NADP(+)复合物中的分子对接以及定点突变，鉴定出与 AKR1B10 结合的抑制剂涉及的非保守残基，包括 Lys125 和 Gln303。
