Department of Biochemistry and Division of Applied Life Science, Gyeongsang National University, Jinju, Republic of Korea.
J Enzyme Inhib Med Chem. 2011 Aug;26(4):535-45. doi: 10.3109/14756366.2010.535795. Epub 2010 Dec 14.
Pancreatic cholesterol esterase (CEase) is a serine hydrolase involved in the hydrolysis of variety of lipids and transport of free cholesterol. In this study, pharmacophore hypotheses based on known inhibitors were generated using common feature pharmacophore generation protocol available in Discovery Studio program. The best pharmacophore model containing two hydrogen bond acceptor and three hydrophobic features was selected and validated. It was further used in screening three diverse chemical databases. Hit compounds were subjected to drug-likeness and molecular docking studies. Four hits, namely SEW00846, NCI0040784, GK03167, and CD10645, were selected based on the GOLD fitness score and interaction with active site amino acids. All hit compounds were further optimized to improve their binding in the active site. The optimized compounds were found to have improved binding at the active site. Strongly binding optimized hits at the active site can act as virtual leads in potent CEase inhibitor designing.
胰腺胆固醇酯酶（CEase）是一种丝氨酸水解酶，参与多种脂质的水解和游离胆固醇的转运。在这项研究中，使用 Discovery Studio 程序中提供的通用特征药效团生成协议，基于已知抑制剂生成药效团假设。选择并验证了包含两个氢键受体和三个疏水特征的最佳药效团模型。进一步将其用于筛选三个不同的化学数据库。对命中化合物进行类药性和分子对接研究。根据 GOLD 适应度得分和与活性位点氨基酸的相互作用，选择了四个命中化合物，即 SEW00846、NCI0040784、GK03167 和 CD10645。所有命中化合物都进一步进行了优化，以改善它们在活性位点的结合。优化后的化合物在活性位点的结合得到了改善。在活性位点与化合物结合较强的优化命中化合物可以作为有效的 CEase 抑制剂设计的虚拟先导化合物。
