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Theoretical studies on benzimidazole derivatives as E. coli biotin carboxylase inhibitors

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Biotin carboxylase (AccC) protein plays an essential role in cell wall biosynthesis in majority of bacterial genera. Inhibition of cell wall biosynthesis might be an ideal way to control the bacterial multiplication in the host system. AccC is one of the promising targets for the antibacterial drugs production. The benzimidazole derivatives are hopeful biotin carboxylase inhibitors, which sensitizes to the Escherichia coli (E. coli) and many other bacterial species too. In steam of developing better benzimidazole derivatives, we describe a quantitative pharmacophore model of benzimidazole derivatives using Phase module of Schrödinger LLC. This model suggested that the following features are essential for ligand binding, i.e., two aromatic rings, two hydrogen bond donors, one hydrogen bond acceptor, and one hydrophobic group. Further, atom-based 3D-QSAR model was constructed using training set of 37 inhibitors. The constructed QSAR model has cross validated co-efficient value of (Q 2) 0.736 and regression co-efficient value of (R 2) 0.937. The external validation indicated that our QSAR model possessed high predicted powers with \( r_{o}^{2} \) value of 0.933, \( r_{\text m}^{2} \) value of 0.876. The best active and least active compounds were docked into the active site of receptor using Glide and hotspots of the active site were analyzed. The QSAR elucidated here for benzimidazole derivatives combined with their binding information will provide an opportunity to explore the chemical space to promote the potency of AccC inhibitors.

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Correspondence to Karthikeyan Muthusamy.

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Nagamani, S., Muthusamy, K., Kirubakaran, P. et al. Theoretical studies on benzimidazole derivatives as E. coli biotin carboxylase inhibitors. Med Chem Res 21, 2169–2180 (2012).

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  • Biotin carboxylase
  • AccC
  • Escherichia coli
  • Phase
  • 3D-QSAR
  • Docking studies
  • External validation