Rational Design and 3D-Pharmacophore Mapping of 5′-Thiourea-Substituted α-Thymidine Analogues as Mycobacterial TMPK Inhibitors
Rational Design and 3D-Pharmacophore Mapping of 5′-Thiourea-Substituted α-Thymidine Analogues as Mycobacterial TMPK Inhibitors
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DOI：
10.1021/ci8004622
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发表时间：
2009-04-01
影响因子：
5.6
通讯作者：
Hopfinger, Anton J.
中科院分区：
文献类型：
--
作者：
Andrade, Carolina H.;Pasqualoto, Kerly F. M.;Hopfinger, Anton J.
胸苷单磷酸激酶 (TMPK) 已成为开发结核分枝杆菌生长抑制剂的有吸引力的靶标。在本研究中，受体独立 (RI) 4D-QSAR 形式已用于开发一组 5'-硫脲取代的 α-胸苷抑制剂的 QSAR 模型和相应的 3D 药效团。为整个训练集和由最有效的抑制剂组成的训练集子集开发了模型。优化的 (RI) 4D-QSAR 模型具有统计显着性（r(2) = 0.90、q(2) = 0.83 整个集、r(2) = 0.86、q(2) = 0.80 高效子集），并且基于测试集预测也具有良好的预测性。最强和最弱的抑制剂，以其各自源自模型的假定活性构象，停靠在 TMPK 晶体结构的活性位点。 QSAR 模型定义的 3D 药效基团位点与结合位点残基的相互作用之间存在牢固的一致性。该模型识别了包含药效团位点的抑制剂的新区域，例如糖-嘧啶环结构和 5'-芳基硫脲部分的区域。可以进一步探索配体的这些新区域，并可能利用它们来识别新的、新颖的、或许更好的 TMPKmt 抗结核抑制剂。此外，这些模型定义的 3D 药效团可用作未来受体依赖性抗结核药物设计的起点，并阐明添加取代基的候选位点，以优化类似抑制剂的 ADMET 特性。
Thymidine monophosphate kinase (TMPK) has emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. In this study the receptor-independent (RI) 4D-QSAR formalism has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 5'-thiourea-substituted alpha-thymidine inhibitors. Models were developed for the entire training set and for a subset of the training set consisting of the most potent inhibitors. The optimized (RI) 4D-QSAR models are statistically significant (r(2) = 0.90, q(2) = 0.83 entire set, r(2) = 0.86, q(2) = 0.80 high potency subset) and also possess good predictivity based on test set predictions. The most and least potent inhibitors, in their respective postulated active conformations derived from the models, were docked in the active site of the TMPK crystallographic structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. This model identifies new regions of the inhibitors that contain pharmacophore sites, such as the sugar-pyrimidine ring structure and the region of the 5'-arylthiourea moiety. These new regions of the ligands can be further explored and possibly exploited to identify new, novel, and, perhaps, better antituberculosis inhibitors of TMPKmt. Furthermore, the 3D-pharmacophores defined by these models can be used as a starting point for future receptor-dependent antituberculosis drug design as well as to elucidate candidate sites for substituent addition to optimize ADMET properties of analog inhibitors.