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<p>Infections of the lungs, central nervous system, eyes, bacteremia as well as a variety of skin and soft tissue infections are commonly caused by the rapidly expanding, multidrug-resistant, non-tuberculous <i>Mycobacterium abscessus</i> complex. In recent studies, malate synthase G (MSG) has been identified as a potential therapeutic drug target in <i>Mycobacterium abscessus</i> subsp<i>. bolletii</i> 50,594 (<i>Mabb</i>). This enzyme is involved in glyoxalate shunt which is an alternative of the TCA cycle by which Mabb survives even in stressful conditions in hosts. The glyoxalate shunt is made up of enzymes isocitrate lyase and malate synthase G. MSG converts glyoxylate into malate which is supplied in the TCA cycle when glucose is not available. In the present study, the three-dimensional structure of malate synthase G of <i>Mabb</i> was predicted using the ModBase web server, followed by stereo-chemical evaluation using SAVES server. To validate the stability of the structure, molecular dynamics simulation was also performed at 50&#xa0;ns. From total energy analysis, it was observed that the structure of MSG was converged and remained stable throughout the simulation. These outcomes were further validated by RMSD, RMSF and RG analysis. In the next step, libraries of the ligand analogs of rifabutin were prepared, as it was reported as a potent drug against MSG. These ligands were utilized for virtual screening by using the protein–ligand docking method with the help of the iGEMDock and AutoDock Vina tools, respectively. The docking results indicate that there are five ligands (CID_131665239, CID_135762947, CID_58352637, CID_10260117 and CID_129637525) which possess lower binding energy toward MSG than rifabutin. Lower energy score reveals higher binding affinity toward the target. Therefore, these five ligands might be developed as potential drug candidates against Mabb. However, wet laboratory experiments are further needed to validate the inhibitory activity of the proposed ligands.</p>

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Molecular modeling, dynamics simulation and docking studies of malate synthase G as a potential drug target against Mycobacterium abscessus subsp. bolletii

  • 期刊论文

  • 发表日期：

    2025年5月31日

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  • Rohit Sahu,
  • Satendra Singh,
  • Budhayash Gautam,
  • Pramod Kumar Yadav

摘要

Infections of the lungs, central nervous system, eyes, bacteremia as well as a variety of skin and soft tissue infections are commonly caused by the rapidly expanding, multidrug-resistant, non-tuberculous Mycobacterium abscessus complex. In recent studies, malate synthase G (MSG) has been identified as a potential therapeutic drug target in Mycobacterium abscessus subsp. bolletii 50,594 (Mabb). This enzyme is involved in glyoxalate shunt which is an alternative of the TCA cycle by which Mabb survives even in stressful conditions in hosts. The glyoxalate shunt is made up of enzymes isocitrate lyase and malate synthase G. MSG converts glyoxylate into malate which is supplied in the TCA cycle when glucose is not available. In the present study, the three-dimensional structure of malate synthase G of Mabb was predicted using the ModBase web server, followed by stereo-chemical evaluation using SAVES server. To validate the stability of the structure, molecular dynamics simulation was also performed at 50 ns. From total energy analysis, it was observed that the structure of MSG was converged and remained stable throughout the simulation. These outcomes were further validated by RMSD, RMSF and RG analysis. In the next step, libraries of the ligand analogs of rifabutin were prepared, as it was reported as a potent drug against MSG. These ligands were utilized for virtual screening by using the protein–ligand docking method with the help of the iGEMDock and AutoDock Vina tools, respectively. The docking results indicate that there are five ligands (CID_131665239, CID_135762947, CID_58352637, CID_10260117 and CID_129637525) which possess lower binding energy toward MSG than rifabutin. Lower energy score reveals higher binding affinity toward the target. Therefore, these five ligands might be developed as potential drug candidates against Mabb. However, wet laboratory experiments are further needed to validate the inhibitory activity of the proposed ligands.