In silico guided design of non-covalent inhibitors of DprE1: synthesis and biological evaluation

• Published in: SAR and QSAR in environmental research Vol. 32; no. 4; pp. 333 - 352
• Main Authors: Verma, H., Choudhary, S., Kumar, M., Silakari, O.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 03-04-2021; Taylor & Francis Ltd
• Subjects: 2-benzoxazolinone; Alcohol Oxidoreductases - chemistry; Amino acids; Antitubercular Agents - chemistry; Bacterial Proteins - chemistry; Benzimidazoles; Benzoxazoles - chemistry; Computer Simulation; DprE1; Humans; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Multidrug resistance; Optimization; Pharmacology; pharmacophore modelling; Quantitative Structure-Activity Relationship; Tuberculosis; XDR-TB; DprE1; XDR-TB; 2-benzoxazolinone; molecular dynamics; pharmacophore modelling
• ISSN: 1062-936X; 1029-046X
• DOI: 10.1080/1062936X.2021.1900390

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.