ABSTRACT

DprE1 is a potential target of resistant tuberculosis (TB), especially multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. 2-benzoxazolinone is a closely related bioisostere of some scaffolds such as benzoxazoles, benzimidazole, benzothiazolinone, and benzothiazoles that have been previously explored against DprE1. Thus, a ligand-based quantitative pharmacophore model (AHRR.8) of DprE1 was developed and this pharmacophore model was utilized in activity profiling of some 2-benzoxazolinones from an in-house database using virtual screening. Obtained hits were subject to molecular docking, molecular dynamics (MD), and MM/GBSA calculations, which resulted in benzoyl-substituted derivatives of 2-benzoxazolinone showing strong interactions with the key amino acid residues in the active site of DprE1. Based on in silico results, the top five hits were duly synthesized and evaluated against the XDR-TB strain. This study is an initial effort to explore 2-benzoxazolinones against XDR-TB, which can be submitted further to lead optimization for refining the results.

摘要

DprE1是耐药结核病（TB）的潜在靶标，尤其是耐多药（MDR）和广泛耐药（XDR）结核病。2-苯并恶唑啉酮是某些支架的紧密相关的生物同工异构体，例如先前已针对DprE1探索的一些支架，例如苯并恶唑，苯并咪唑，苯并噻唑啉酮和苯并噻唑。因此，开发了DprE1的基于配体的定量药效团模型（AHRR.8），并将该药效团模型用于内部数据库中使用虚拟筛选的某些2-苯并恶唑啉酮的活性分析。对获得的命中进行分子对接，分子动力学（MD）和MM / GBSA计算，结果导致2-苯并恶唑啉酮的苯甲酰基取代的衍生物与DprE1活性位点中的关键氨基酸残基表现出强烈的相互作用。根据计算机分析结果，适当地综合了前五名，并针对XDR-TB菌株进行了评估。这项研究是探索针对XDR-TB的2-苯并恶唑啉酮的一项初步工作，可以进一步提交该文献以导致优化以完善结果。