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Identification of dual Acetyl-CoA carboxylases 1 and 2 inhibitors by pharmacophore based virtual screening and molecular docking approach

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Abstract

Acetyl-CoA carboxylase (ACC) is a crucial metabolic enzyme that plays a vital role in obesity-induced type 2 diabetes and fatty acid metabolism. To identify dual inhibitors of Acetyl-CoA carboxylase1 and Acetyl-CoA carboxylase2, a pharmacophore modelling approach has been employed. The best HypoGen pharmacophore model for ACC2 inhibitors (Hypo1_ACC2) consists of one hydrogen bond acceptor, one hydrophobic aliphatic and one hydrophobic aromatic feature, whereas the best pharmacophore (Hypo1_ACC1) for ACC1 consists of one additional hydrogen-bond donor (HBD) features. The best pharmacophore hypotheses were validated by various methods such as test set, decoy set and Cat-Scramble methodology. The validated pharmacophore models were used to screen several small-molecule databases, including Specs, NCI, ChemDiv and Natural product databases to identify the potential dual ACC inhibitors. The virtual hits were then subjected to several filters such as estimated \(\text{ IC}_{50}\) value, quantitative estimation of drug-likeness and molecular docking analysis. Finally, three novel compounds with diverse scaffolds were selected as potential starting points for the design of novel dual ACC inhibitors.

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Acknowledgments

The authors acknowledge financial support from Department of Science and Technology (DST), New Delhi.

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Authors and Affiliations

  1. Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sect-67, S.A.S. Nagar, Punjab, 160 062, India

    Anuseema Bhadauriya, Gaurao V. Dhoke, Rahul P. Gangwal, Mangesh V. Damre & Abhay T. Sangamwar

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  1. Anuseema Bhadauriya
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  2. Gaurao V. Dhoke
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  3. Rahul P. Gangwal
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  4. Mangesh V. Damre
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  5. Abhay T. Sangamwar
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Corresponding author

Correspondence to Abhay T. Sangamwar.

Additional information

Anuseema Bhadauriya and Gaurao V. Dhoke contributed equally to this study.

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Bhadauriya, A., Dhoke, G.V., Gangwal, R.P. et al. Identification of dual Acetyl-CoA carboxylases 1 and 2 inhibitors by pharmacophore based virtual screening and molecular docking approach. Mol Divers 17, 139–149 (2013). https://doi.org/10.1007/s11030-013-9425-2

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  • DOI: https://doi.org/10.1007/s11030-013-9425-2

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