Dessalew Nigus, Bharatam Prasad V
Department of Pharmaceutical Chemistry, School of Pharmacy, Addis Ababa University, PO Box 1176, Addis Ababa, Ethiopia.
Chem Biol Drug Des. 2006 Sep;68(3):154-65. doi: 10.1111/j.1747-0285.2006.00430.x.
Glycogen synthase kinase-3 is a serine/threonine kinase that has attracted significant drug discovery attention in recent years. To investigate the identification of new potential glycogen synthase kinase-3 inhibitors, a pharmacophore mapping study was carried out using a set of 21 structurally diverse glycogen synthase kinase-3 inhibitors. A hypothesis containing four features: two hydrophobic, one hydrogen bond donor and another hydrogen bond acceptor was found to be the best from the 10 common feature hypotheses produced by HipHop module of Catalyst. The best hypothesis has a high cost of 156.592 and higher best fit values were obtained for the 21 inhibitors using this best hypothesis than the other HipHop hypotheses. The best hypothesis was then used to screen electronically the NCI2000 database. The hits obtained were docked into glycogen synthase kinase-3beta active site. A total of five novel potential leads were proposed after: (i) visual examination of how well they dock into the glycogen synthase kinase-3beta-binding site, (ii) comparative analysis of their FlexX, G-Score, PMF-Score, ChemScore and D-Scores values, (iii) comparison of their best fit value with the known inhibitors and (iv) examination of the how the hits retain interactions with the important amino acid residues of glycogen synthase kinase-3beta-binding site.
糖原合酶激酶-3是一种丝氨酸/苏氨酸激酶，近年来在药物研发方面备受关注。为了研究新型潜在糖原合酶激酶-3抑制剂的鉴定，利用一组21种结构各异的糖原合酶激酶-3抑制剂进行了药效团映射研究。在由Catalyst的HipHop模块生成的10个常见特征假设中，发现一个包含四个特征的假设是最佳的：两个疏水基团、一个氢键供体和另一个氢键受体。最佳假设的成本较高，为156.592，使用该最佳假设对21种抑制剂获得的最佳拟合值高于其他HipHop假设。然后使用最佳假设对NCI2000数据库进行电子筛选。将获得的命中物对接至糖原合酶激酶-3β的活性位点。在经过以下步骤后共提出了5种新型潜在先导化合物：(i) 直观检查它们对接至糖原合酶激酶-3β结合位点的效果；(ii) 对它们的FlexX、G-Score、PMF-Score、ChemScore和D-Scores值进行比较分析；(iii) 将它们的最佳拟合值与已知抑制剂进行比较；(iv) 检查命中物与糖原合酶激酶-3β结合位点重要氨基酸残基的相互作用情况。
