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The Dual-Targeting Activity of the Metabolite Substrate of Para-amino Salicyclic Acid in the Mycobacterial Folate Pathway: Atomistic and Structural Perspectives.
The Protein Journal ( IF 3 ) Pub Date : 2020-02-21 , DOI: 10.1007/s10930-020-09885-1 Clement Agoni 1 , Pritika Ramharack 1 , Elliasu Y Salifu 1 , Mahmoud E S Soliman 1
The Protein Journal ( IF 3 ) Pub Date : 2020-02-21 , DOI: 10.1007/s10930-020-09885-1 Clement Agoni 1 , Pritika Ramharack 1 , Elliasu Y Salifu 1 , Mahmoud E S Soliman 1
Affiliation
Therapeutic targeting of folate biosynthetic pathway has recently been explored as a viable strategy in the treatment of tuberculosis. The bioactive metabolite substrate of Para-amino salicyclic acid (PAS-M) reportedly dual-targets dihydrofolate reductase (DHFR) and flavin-dependent thymidylate synthase (FDTS), two essential enzymes in folate biosynthetic pathway. However, the molecular mechanisms and structural dynamics of this dual inhibitory activity of the PAS-M remain elusive. Molecular dynamics simulations revealed that binding of PAS-M towards DHFR is characterized by a recurrence of strong conventional hydrogen bond interactions between a peculiar DHFR binding site residue (Asp27) and the 2-amino-decahydropteridin-4-ol group of PAS-M. Similarly, the binding of PAS-M towards FDTS also involved consistent strong conventional hydrogen bond interactions between some specific residues (Tyr101, Arg172, Thr4, Gln103, Arg87 and Gln106) and, the 2-amino-decahydropteridin-4-ol group, thus establishing the cruciality of the group. Structural dynamics of the bound complexes of both enzymes revealed that, upon binding, PAS-M is anchored at the entrance of hydrophobic pockets by strong hydrogen bond interactions while the rest of the structure gains access to deeper hydrophobic residues to engage in favorable interactions. Further analysis of atomistic changes of both enzymes showed increased C-α atom deviations as well as an increase C-α atoms radius of gyration consistent with structural disorientations. These conformational changes possibly interfered with the biological functions of the enzymes and hence their inhibition as experimentally reported. Structural Insights provided could open up a novel paradigm of structure-based design of multi-targeting inhibitors of biological targets in the folate biosynthetic pathway toward tuberculosis therapy.
中文翻译:
对氨基水杨酸代谢产物底物在分枝杆菌叶酸途径中的双重靶向活性:原子和结构的观点。
叶酸生物合成途径的靶向治疗最近已被视为治疗结核病的可行策略。据报道,对氨基水杨酸(PAS-M)的生物活性代谢物底物具有双靶点二氢叶酸还原酶(DHFR)和黄素依赖性胸苷酸合酶(FDTS),这是叶酸生物合成途径中的两种必需酶。然而,PAS-M双重抑制活性的分子机制和结构动力学仍然难以捉摸。分子动力学模拟显示,PAS-M与DHFR的结合的特征是,独特的DHFR结合位点残基(Asp27)与PAS-M的2-氨基-十氢蝶呤-4-醇基团之间发生了很强的常规氢键相互作用。同样,PAS-M与FDTS的结合还涉及某些特定残基(Tyr101,Arg172,Thr4,Gln103,Arg87和Gln106)与2-氨基十氢蝶呤-4-醇基团之间一致的常规氢键相互作用,从而建立了小组的重要性。两种酶结合复合物的结构动力学表明,结合后,PAS-M通过强大的氢键相互作用锚固在疏水性囊袋的入口,而结构的其余部分则可以进入更深的疏水性残基以参与有利的相互作用。两种酶的原子性变化的进一步分析显示,与结构位错一致,C-α原子偏差增加,C-α原子回转半径增加。这些构象变化可能会干扰酶的生物学功能,因此,如实验报道的,其抑制作用。提供的“结构见解”可以开辟一种基于结构的叶酸生物合成途径中朝向结核病治疗的生物靶标多靶标抑制剂设计新范式。
更新日期:2020-02-21
中文翻译:
对氨基水杨酸代谢产物底物在分枝杆菌叶酸途径中的双重靶向活性:原子和结构的观点。
叶酸生物合成途径的靶向治疗最近已被视为治疗结核病的可行策略。据报道,对氨基水杨酸(PAS-M)的生物活性代谢物底物具有双靶点二氢叶酸还原酶(DHFR)和黄素依赖性胸苷酸合酶(FDTS),这是叶酸生物合成途径中的两种必需酶。然而,PAS-M双重抑制活性的分子机制和结构动力学仍然难以捉摸。分子动力学模拟显示,PAS-M与DHFR的结合的特征是,独特的DHFR结合位点残基(Asp27)与PAS-M的2-氨基-十氢蝶呤-4-醇基团之间发生了很强的常规氢键相互作用。同样,PAS-M与FDTS的结合还涉及某些特定残基(Tyr101,Arg172,Thr4,Gln103,Arg87和Gln106)与2-氨基十氢蝶呤-4-醇基团之间一致的常规氢键相互作用,从而建立了小组的重要性。两种酶结合复合物的结构动力学表明,结合后,PAS-M通过强大的氢键相互作用锚固在疏水性囊袋的入口,而结构的其余部分则可以进入更深的疏水性残基以参与有利的相互作用。两种酶的原子性变化的进一步分析显示,与结构位错一致,C-α原子偏差增加,C-α原子回转半径增加。这些构象变化可能会干扰酶的生物学功能,因此,如实验报道的,其抑制作用。提供的“结构见解”可以开辟一种基于结构的叶酸生物合成途径中朝向结核病治疗的生物靶标多靶标抑制剂设计新范式。