Owono Owono Luc Calvin, Keita Melalie, Megnassan Eugene, Frecer Vladimir, Miertus Stanislav
Laboratory for Simulations and Biomolecular Physics, Advanced Teachers Training College, University of Yaoundé I, P.O. Box 47, Yaoundé, Cameroon ; Centre for Atomic Molecular Physics and Quantum Optics (CEPAMOQ), University of Douala, P.O. Box 8580, Douala, Cameroon ; International Centre for Science and High Technology, UNIDO, Area Science Park, Padriciano 99, 34012 Trieste, Italy.
Tuberc Res Treat. 2013;2013:670836. doi: 10.1155/2013/670836. Epub 2013 Mar 24.
We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmt cocrystallized with the natural substrate deoxythymidine monophosphate (dTMP) (1GSI) for a training set of 15 thymidine analogues (TMDs) with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation (ΔΔG com) and K i values explains 94% of the TMPKmt inhibition (pK i = -0.2924ΔΔG com + 3.234; R (2) = 0.94) by variation of the computed ΔΔG com and 92% for the pharmacophore (PH4) model (pK i = 1.0206 × pK i (pred) - 0.0832, R (2) = 0.92). The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5'-position of the ribose. The best inhibitor reached a predicted K i of 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents.
我们在此通过基于结构的分子设计，设计了新型纳摩尔级抗结核药物，即结核分枝杆菌胸苷单磷酸激酶（TMPKmt）的抑制剂。利用与天然底物脱氧胸苷单磷酸（dTMP）共结晶的TMPKmt晶体结构（1GSI），为一组15个具有已知活性的胸苷类似物（TMDs）构建了TMPKmt-抑制剂复合物的3D模型，以建立一个相互作用的QSAR模型，确定络合自由能与生物活性之间的相关性。随后通过3D QSAR药效团生成对该模型的可预测性进行了验证。从该模型获得的结构信息用于设计新的亚纳摩尔级胸苷类似物。通过分子模拟研究，络合自由能（ΔΔG com）与K i值之间的一致性解释了94%的TMPKmt抑制作用（pK i = -0.2924ΔΔG com + 3.234；R (2) = 0.94），通过计算得到的ΔΔG com的变化以及药效团（PH4）模型的92%（pK i = 1.0206 × pK i (预测值) - 0.0832，R (2) = 0.92）。对活性位点残基贡献的分析表明，嘧啶环的5位以及核糖5'位的各种基团可进行取代。最佳抑制剂的预测K i值达到0.155 nM。通过结合使用分子模拟和PH4药效团的计算方法有助于靶向药物设计，为新型抗结核药物的合成和活性预测提供有价值的信息。
