Skip to content

In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase: HQSAR, CoMSIA and molecular dynamics simulations

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)775-800
Number of pages27
JournalSAR and QSAR in Environmental Research
Volume30
Issue number11
Early online date14 Oct 2019
DOIs
DateAccepted/In press - 17 Aug 2019
DateE-pub ahead of print - 14 Oct 2019
DatePublished (current) - 2 Nov 2019

Abstract

Mycobacterium tuberculosis DNA gyrase subunit B (GyrB) has been identified as a promising target for rational drug design against fluoroquinolone drug-resistant tuberculosis. In this study, we attempted to identify the key structural feature for highly potent GyrB inhibitors through 2D-QSAR using HQSAR, 3D-QSAR using CoMSIA and molecular dynamics (MD) simulations approaches on a series of thiazole urea core derivatives. The best HQSAR and CoMSIA models based on IC50 and MIC displayed the structural basis required for good activity against both GyrB enzyme and mycobacterial cell. MD simulations and binding free energy analysis using MM-GBSA and waterswap calculations revealed that the urea core of inhibitors has the strongest interaction with Asp79 via hydrogen bond interactions. In addition, cation-pi interaction and hydrophobic interactions of the R2 substituent with Arg82 and Arg141 help to enhance the binding affinity in the GyrB ATPase binding site. Thus, the present study provides crucial structural features and a structural concept for rational design of novel DNA gyrase inhibitors with improved biological activities against both enzyme and mycobacterial cell, and with good pharmacokinetic properties and drug safety profiles.

    Research areas

  • binding free energy, CoMSIA, DNA gyrase, GyrB inhibitors, HQSAR, MD simulations

Documents

Documents

  • Full-text PDF (author’s accepted manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Taylor & Francis at https://www.tandfonline.com/doi/full/10.1080/1062936X.2019.1658218 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 1.51 MB, PDF document

    Embargo ends: 14/10/20

    Request copy

DOI

View research connections

Related faculties, schools or groups