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Publication - Professor Adrian Mulholland

    In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase

    HQSAR, CoMSIA and molecular dynamics simulations

    Citation

    Kamsri, P, Punkvang, A, Hannongbua, S, Suttisintong, K, Kittakoop, P, Spencer, J, Mulholland, AJ & Pungpo, P, 2019, ‘In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase: HQSAR, CoMSIA and molecular dynamics simulations’. SAR and QSAR in Environmental Research, vol 30., pp. 775-800

    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.

    Full details in the University publications repository