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Receptor based 3D-QSAR to identify putative binders of Mycobacterium tuberculosis Enoyl acyl carrier protein reductase

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Abstract

In the current study, the applicability and scope of 3D-QSAR models (CoMFA and CoMSIA) to complement virtual screening using 3D pharmacophore and molecular docking is examined and applied to identify potential hits against Mycobacterium tuberculosis Enoyl acyl carrier protein reductase (MtENR). Initially CoMFA and CoMSIA models were developed using series of structurally related arylamides as MtENR inhibitors. Docking studies were employed to position the inhibitors into MtENR active site to derive receptor based 3D-QSAR models. Both CoMFA and CoMSIA yielded significant cross validated q2 values of 0.663 and 0.639 and r2 values of 0.989 and 0.963, respectively. The statistically significant models were validated by a test set of eight compounds with predictive r2 value of 0.882 and 0.875 for CoMFA and CoMSIA. The contour maps from 3D-QSAR models in combination with docked binding structures help to better interpret the structure activity relationship. Integrated with CoMFA and CoMSIA predictive models structure based (3D-pharmacophore and molecular docking) virtual screening have been employed to explore potential hits against MtENR. A representative set of 20 compounds with high predicted IC50 values were sorted out in the present study.

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Acknowledgments

This manuscript is CDRI communication number 7706. This work was supported by the grants from Council of Scientific and Industrial Research (CSIR-India) funded network project NWP0034 (Validation of identified screening models and development of new alternative models for evaluation of new drug entities). Ashutosh Kumar thanks CSIR for fellowship.

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  1. Molecular and Structural Biology Division, Central Drug Research Institute, Lucknow, 226 001, India

    Ashutosh Kumar & Mohammad Imran Siddiqi

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  1. Ashutosh Kumar
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  2. Mohammad Imran Siddiqi
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Correspondence to Mohammad Imran Siddiqi.

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Kumar, A., Siddiqi, M.I. Receptor based 3D-QSAR to identify putative binders of Mycobacterium tuberculosis Enoyl acyl carrier protein reductase. J Mol Model 16, 877–893 (2010). https://doi.org/10.1007/s00894-009-0584-0

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  • DOI: https://doi.org/10.1007/s00894-009-0584-0

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