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3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis
Drug Discovery Division, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong, Daejeon 305-600, Korea
College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, Daejeon 306-350, Korea
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 24 September 2013; in revised form: 4 November 2013 / Accepted: 6 November 2013 / Published: 8 November 2013
Abstract: Inhibitory activities of monocyclic nitroimidazoles against Mycobacterium tuberculosis (Mtb) deazaflavin-dependent nitroreductase (DDN) were modeled by using docking, pharmacophore alignment and comparative molecular similarity indices analysis (CoMSIA) methods. A statistically significant model obtained from CoMSIA was established based on a training set using pharmacophore-based molecular alignment. The leave-one out cross-validation correlation coefficients q2 (CoMSIA) were 0.681. The CoMSIA model had a good correlation (/CoMSIA = 0.611) between the predicted and experimental activities against excluded test sets. The generated model suggests that electrostatic, hydrophobic and hydrogen bonding interactions all play important roles for interaction between ligands and receptors. The predicted cell wall permeability (logPapp) for substrates with high inhibitory activity against Mtb were investigated. The distribution coefficient (logD) range was 2.41 < logD < 2.89 for the Mtb cell wall membrane permeability. The larger the polar surface area is, the better the permeability is. A larger radius of gyration (rgry) and a small fraction of rotatable bonds (frtob) of these molecules leads to higher cell wall penetration ability. The information obtained from the in silico tools might be useful in the design of more potent compounds that are active against Mtb.
Keywords: antitubercular activity; monocyclic nitroimidazoles; Mycobacterium tuberculosis; 3D-QSAR; cell wall permeability
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MDPI and ACS Style
Lee, S.-H.; Choi, M.; Kim, P.; Myung, P.K. 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis. Molecules 2013, 18, 13870-13885.
Lee S-H, Choi M, Kim P, Myung PK. 3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis. Molecules. 2013; 18(11):13870-13885.
Lee, Sang-Ho; Choi, Minsung; Kim, Pilho; Myung, Pyung K. 2013. "3D-QSAR and Cell Wall Permeability of Antitubercular Nitroimidazoles against Mycobacterium tuberculosis." Molecules 18, no. 11: 13870-13885.