ABSTRACT Different resistant strains of M. tuberculosis (Mtb) highlight the urgent need of novel anti-tubercular drugs. In mycobacteria, decaprenyl-phosphoryl-β-D-ribose 2’-oxidase (DprE1) is an appealing enzyme to target as it is involved in the biosynthesis of cell wall component arabinogalactan.1, 3-benzothiazin-4-ones (BTZs) based drugs are promising irreversible inhibitors of DprE1. However, a single point mutation of Cys387Ser in DprE1 results in the development of resistance to these drugs. Herein, we made an effort to decode the molecular mechanism of Cys387Ser DprE1 mutation associated resistance in Mtb against BTZs using different in silico techniques. Since the 3D crystal structure of mutant Cys387Ser protein is not yet been solved, thus the homology model was also developed using 4P8N as a template protein with 99.8% homology with the target protein. The computational results suggested that the factors like HOMO–LUMO energy gap, Burgi-Dunitz angle and distance support the covalent inhibition of wild DprE1 by 1, 3-benzothiazin-4-ones class of drugs, using BTZ043 as a reference drug and the same factors support the cause of resistance in case of Cys387Ser mutation. On the basis of these results, it was concluded that BTZ043 can efficiently inhibit the wild type DprE1 than mutant DprE1.

中文翻译：

---

使用 BTZ043 作为参考药物，解码与基于 1, 3-苯并噻嗪-4-酮 (Btzs) 的 DprE1 抑制剂的突变相关抗性的分子机制的特征

摘要 结核分枝杆菌 (Mtb) 的不同耐药菌株凸显了对新型抗结核药物的迫切需求。在分枝杆菌中，decaprenyl-phosphoryl-β-D-ribose 2'-oxidase (DprE1) 是一种有吸引力的靶向酶，因为它参与细胞壁成分阿拉伯半乳聚糖的生物合成。1, 3-benzothiazin-4-ones (BTZs)基于药物是有前途的 DprE1 的不可逆抑制剂。然而，DprE1 中 Cys387Ser 的单点突变导致对这些药物产生耐药性。在此，我们努力使用不同的计算机技术解码 Mtb 中 Cys387Ser DprE1 突变相关抗 BTZ 的分子机制。由于突变体 Cys387Ser 蛋白的 3D 晶体结构尚未解决，因此还使用 4P8N 作为模板蛋白与 99 建立了同源模型。与目标蛋白的同源性为 8%。计算结果表明 HOMO-LUMO 能隙、Burgi-Dunitz 角和距离等因素支持 1, 3-benzothiazin-4-ones 类药物对野生 DprE1 的共价抑制，使用 BTZ043 作为参考药物，同样在 Cys387Ser 突变的情况下，一些因素支持产生抗性的原因。基于这些结果，可以得出结论，BTZ043 可以比突变体 DprE1 更有效地抑制野生型 DprE1。