Discovery of natural inhibitors targeting 2 - trans enoyl acyl carrier protein reductase in Mycobacterium tuberculosis by structure based drug designing

Saurov Mahanta, Purvita Chowdhury, Shamsun Nahar, Bhaben Tanti, P. J. Handique*

Abstract


Evolution and the rapid spread of the multidrug resistant Mycobacterium tuberculosis (Mtb) have posed a serious crisis. Moreover, the available first line drugs also confer adverse effects on the patients suffering from tuberculosis (TB) thus making the cure increasingly difficult. Thus the search of novel and potent natural compounds targeting anti-tubercular agents has become inevitable. Here, we report identification of potential natural anti-tubercular candidates targeting Mtb 2-Trans Enoyl Acyl Carrier Protein Reductase (InhA) of the fatty acid pathway using structure based drug designing. In the present study, we selected a total of 154 compounds from three plants i.e. Ginkgo biloba, Neem (Azadirachta indica) and Tea (Camellia sinensis) which were obtained from PubChem Compounds. These compounds were subjected to Lipinski’s rule of five and drug likeness filters. Finally, the compounds were docked at the active site of Mtb InhA (PDB code: 3FNE) using AutoDock Vina to select inhibitors with favourable interactions. The structure based ligand receptor docking aided in the identification of a number of natural candidates which had high binding affinities against Mtb InhA. Thus, these molecules could potentially inhibit Mtb InhA and succor to the development of lead compounds in the experimental drug discovery of anti-tuberculars.

Keywords


InhA; natural compounds; docking; Mycobacterium tuberculosis (Mtb); drug designing

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References


Anonymous, World Health Organisation: Global tuberculosis control: WHO report (2013).

Banerjee, A., Dubnau, E., Quemard, A., Balasubramanian, V., Um, K.S., Wilson, T., Collins, D., de Lisle, G., Jacobs Jr, W.R., InhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 263, (1994): 227–230.

Brown, A.K., Papaemmanouil, A., Bhowruth, V., Bhatt, A., Dover, L.G., Besra, G.S., Flavonoid inhibitors as novel antimycobacterial agents targeting Rvo636, a putative dehydratase enzyme involved in Mycobacterium tuberculosis fatty acid synthase II. Microbiology. 153, (2007): 3314-3322.

Dessen, A., Quemard, A., Blanchard, J.S., Jacobs, W.R., Sacchettini, J.C., Crystal structure and function of the isoniazid target of in Mycobacterium tuberculosis. Science. 267, (1995): 1638–1641.

Gbotolorun, S.C., Osinubi, A.A., Noronha, C.C., Okanlawon, A.O., Antifertility potential of Neem flower extract on adult female Sprague-Dawley rats. Afr Health Sci. 8, (2008): 168–173.

Hasan, S., Daugelat, S., Rao, P.S.S., Schreiber, M., Prioritizing Genomic Drug Targets in Pathogens: Application to Mycobacterium tuberculosis. PLoS Comput Biol. 2.6, (2006): e61. doi: 10.1371/journal.pcbi.0020061.

Kakati, D., Mahanta, S., Tanti, B., In-silico comparative structural modeling of carbonic anhydrase of the marine diatom Thalassiosira pseudonana. Journal of Research in Bioinformatics. 1, (2012): 9-15.

Lalitha, P., Sivakamasundari, S., Calculation of Molecular lipophilicity and drug likeness for few heterocycles. Orintal J. of Chemistry. 26, (2010): 135-141.

Laurie, A.T., Jackson, R.M., Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinformatics. 21.9, (2005): 1908-16.

Lim, Y.M., Flavin, M.T., Cassidy, C.S., Mar, A., Chen, F.C., Biflavonoids as antituberculosis agents. Bioorg Med Chem Lett. 11, (2001): 2101-2104.

Lin, Y.M., Zhou, Y., Flavin, M.T., Zhou, L.M., Nie, W., Chen, F.C., Chalcones and flavonoids as anti-tuberculosis agents. Bioorg Med Chem. 10, (2002): 2795-2802.

Lipinski, C.A., Drug- like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 44, (2000): 235 – 249.

Morris, G.M., Huey, R., Olson, A.J., Using AutoDock for ligand-receptor docking. Curr Protoc Bioinformatics. Chapter 8(Unit 8), (2008): 14.

Nunn, P., Williams, B., Floyd, K., Dye, C., Elzinga, G., Raviglione, M., Tuberculosis control in the era of HIV. Nat Rev Immunol. 5, (2005): 819-826.

Pedretti, A., Villa, L., Vistoli, G., VEGA - An open platform to develop chemo-bioinformaitcs applications, using plug-in architechture and script programming. Journal of Molecular Aided Drug Designing. 18, (2004): 167-173.

Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenbaltt, D.N., Meng, E.C., Ferrin, T.E., UCSF Chimera- A visualization system for exploratory research and analysis. J. Comput. Chem. 25.13, (2004): 1605- 1612.

Quemard, A., Sacchettini, J.C., Dessen, A., Vilcheze, C., Bittman, R., Jacobs, W.R., Blanchard, J.S., Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry 34, (1995): 8235–8241.

Raman, K., Yeturu, K., Chandra, N., Target TB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis. BMC Systems Biology. 2, (2008):109.

Sadowski, J., Gasteiger, J., Klebe G., Comparision of Automatic Three-Dimensional Model Builders Using 639 X-ray Structures. J. Chem. Inf. Comput. Sci. 34, (1994): 1000-1008.

Schroeder, E.K., de Souza, N., Santos, D.S., Blanchard, J.S., Basso, L.A., Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis. Curr Pharm Biotechnol. 3, (2002): 197-225.

Schumacher, M., Cerella, C., Reuter, S., Dicato, M., Diederic, M., Anti-inflammatory, pro-apoptotic, and anti-proliferative effects of a methanolic neem (Azadirachta indica) leaf extract are mediated via modulation of the nuclear factor-κB pathway. Genes Nutr. 6, (2011):149–160.

Sharma, D.K., Pharmacological properties of flavanoids including flavonolignans-Integration of petrocrops with drug development from plants. Journal of Scientific and Industrial Research. 65, (2006): 477-484.

Sullivan, T.J., Truglio, J.J., Boyne, M.E., Novichenok, P., Zhang, X., Stratton, C.F., Li, H.J., Kaur, T., Amin, A., Johnson, F., Slayden, R.A., Kisker, C., Tonge, P.J., High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis. ACS Chem Biol. 1, (2006): 43–53.

Trott, O., Olson, A.J., Auto Dock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 31.2, (2010): 455-461.

Vilchèze, C., Wang, F., Arai, M., Hazbón, M.H., Colangeli, R., Kremer, L., Weisbrod, T.R., Alland, D., Sacchettini, J.C., Jacobs Jr, W.R., Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid. Nat Med. 12, (2006): 1027-1029.

Wang, H., Ng, T.B., Ginkbilobin, a novel antifungal protein from Ginkgo biloba seeds with sequence similarity to embryo-abundant protein. Biochem Biophys Res Commun. 279, (2000): 407-11.




DOI: https://doi.org/10.21746/aps.2016.09.002



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