Target related in silico analysis of Bergenin and tuberculosis management
Keywords:Tuberculosis, Bergenin, in silico, proteomics
Introduction and Aim: Tuberculosis (TB) is a global health concern, claiming two million lives every year. Although an oldest known human infectious disease, researcher is falling short of giving out an effective and reliable vaccine or therapy. The current antimycobacterial drugs include Isoniazid, Ethambutol, Rifampicin and Pyrazinemamide available in market, but most of these are known to have certain adverse effects. Hence there is an increase in demand for natural products with anti-tuberculosis activity with no or limited side effects. Indian traditional systems of medicine have a plethora of promising plants for treatment of tuberculosis, of which Bergenin is the most well established and extensively used compound. The main aim of this research was to investigate the role of Bergenin as an anti-tuberculosis agent with the help of in-silico analysis and protein interaction studies.
Materials and Methods: In the present study 04 known 3-dimensional crystallized anti-tubercular drug target is considered and retrieved from PDB. Drug Isoniazid, Ethambutol, Rifampicin, Pyrazineamide and phytochemical Bergenin were retrieved, sketched and geometrically optimized. Molecular docking is carried to understand the binding mode and its core interactions. ADMET properties were calculated in assessment of the toxicity. Protein-protein interactions and enrichment analysis is carried out to understand the biological process involved with rpsA protein.
Results: In the present study other than Rifampicin, Bergenin reported with better binding energy and similar pharmacophoric interaction pattern as compared to all the 04 indigenous inhibitors. The PPI network and enrichment analysis predicts the plausible biological process involved with rpsA protein and can be further targeted in treatment of tuberculosis.
Conclusion: The results showed that Bergenin was better than and competent with the existing drugs and can be used as an anti-tuberculosis agent if studied in-vitro and in-vivo for its activity.
WHO. Global Tuberculosis Report. Geneva. 2015.
WHO. Tuberculosis Vaccine Development. Geneva. 2015.
Davies, J. Origins and evolution of antibiotic resistance. Microbiologia. 1996 Mar; 12(1): 9-16.
Byrd, T. F., Davis, L. E. Multidrug-resistant tuberculous meningitis. Curr Neurol Neurosci Rep. 2007 Nov; 7(6): 470-475.
Fountain, F. F., Tolley, E., Chrisman, C. R., Self, T. H. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic. Chest. 2005 Jul; 128(1): 116-123.
Cox, H. S., Morrow, M., Deutschmann, P. W. Long term efficacy of DOTS regimens for tuberculosis: systematic review. BMJ. 2008 Mar 1; 336(7642): 484-487.
Iseman, M. D. Treatment of multidrug-resistant tuberculosis. N Engl J Med. 1993 Sep 9; 329(11): 784-791.
WHO. Fixed-dose combination tablets for the treatment of tuberculosis: report of an informal meeting held in Geneva. 1999.
Oradell, N. editor. Rifadin (Hoechst Marion Roussel). In: PDR Physicians’ desk reference. 54th ed. Medical Economics Data; 2000. p. 1379-1382.
Reed, M. D., Blumer, J. L. Clinical pharmacology of antitubercular drugs. Pediatr Clin North Am. 1983 Feb; 30(1): 177-193.
Houston, S., Fanning, A. Current and potential treatment of tuberculosis. Drugs. 1994 Nov; 48(5): 689-708.
Oradell, N. editor. Myambutol (Lederle). In: IPDR Physicians’ desk reference. 54th ed. Medical Economics Data; 2000. p. 1538-1539.
Oradell, N. editor. Pyrazinamide (Lederle). In: PDR Physicians’ desk reference. 54th ed. Medical Economics Data; 2000. p. 1543-1544.
Steele, M. A., Des Prez, R. M. The role of pyrazinamide in tuberculosis chemotherapy. Chest. 1988 Oct; 94(4): 845-850.
Girling, D. J. The role of pyrazinamide in primary chemotherapy for pulmonary tuberculosis. Tubercle. 1984 Mar; 65(1): 1-4.
Paswan, S. K., Gautam, A., Verma, P., Rao, C. V., Sidhu, O. P., Singh, A. P., et al., The Indian Magical Herb “Sanjeevni” (Selaginella bryopteris L.) - A Promising Anti-inflammatory Phytomedicine for the Treatment of Patients with Inflammatory Skin Diseases. J pharmacopuncture. 2017 Jun; 20(2): 93-99.
Sandy, J., Holton, S., Fullam, E., Sim, E., Noble, M. Binding of the anti-tubercular drug isoniazid to the arylamine N-acetyltransferase protein from Mycobacterium smegmatis. Protein Sci. 2005 Mar; 14(3): 775-782.
Alderwick, L. J., Lloyd, G. S., Ghadbane, H., May, J. W., Bhatt, A., Eggeling, L., et al., The C-terminal domain of the Arabinosyltransferase Mycobacterium tuberculosis EmbC is a lectin-like carbohydrate binding module. PLoS Pathog. 2011 Feb; 7(2): e1001299.
Liu, L-K., Abdelwahab, H., Martin Del Campo, J. S., Mehra-Chaudhary, R., Sobrado, P., Tanner, J. J. The Structure of the Antibiotic Deactivating, N-hydroxylating Rifampicin Monooxygenase. J Biol Chem. 2016 Oct 7; 291(41): 21553-21562.
Yang, J., Liu, Y., Bi, J., Cai, Q., Liao, X., Li, W., et al. Structural basis for targeting the ribosomal protein S1 of Mycobacterium tuberculosis by pyrazinamide. Mol Microbiol. 2015 Mar; 95(5): 791-803.
Kim, S., Thiessen, P. A., Bolton, E. E., Chen, J., Fu, G., Gindulyte, A., et al., PubChem Substance and Compound databases. Nucleic Acids Res. 2016 Jan 4; 44(D1): D1202-D1213.
Chemsketch [Internet]. 2018.
Rappe, A. K., Casewit, C. J., Colwell, K. S., Goddard, W. A., Skiff, W. M. UFF, a full periodic table force field for molecular mechanics and molecular dynamics simulations. J Am Chem Soc. 1992 Dec; 114(25): 10024-10035.
Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., et al., AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009 Dec; 30(16): 2785-2791.
Trott, O., Olson, A. J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2009; NA-NA.
Daina, A., Michielin, O., Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7: 42717.
Cheng, F., Li, W., Zhou, Y., Shen, J., Wu, Z., Liu, G., et al., admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model. 2012 Nov 26; 52(11): 3099-3105.
Szklarczyk, D., Morris, J. H., Cook, H., Kuhn, M., Wyder, S., Simonovic, M., et al., The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017; 45(D1): D362-D368.
Mohamad, S., Ismail, N. N., Parumasivam, T., Ibrahim, P., Osman, H. A., Wahab, H. Antituberculosis activity, phytochemical identification of Costus speciosus (J. Koenig) Sm., Cymbopogon citratus (DC. Ex Nees) Stapf., and Tabernaemontana coronaria (L.) Willd. and their effects on the growth kinetics and cellular integrity of Mycobacteri. BMC Complement Altern Med. 2018 Jan 8; 18(1): 5.
Umesh, H. R., Ramesh, K. V., Devaraju, K. S. Molecular docking studies of phytochemicals against trehalose–6–phosphate phosphatases of pathogenic microbes. Beni-Suef Univ J Basic Appl Sci. 2020 Dec 3; 9(1): 5.
Kumar, S., Sharma, C., Kaushik, S. R., Kulshreshtha, A., Chaturvedi, S., Nanda, R. K., et al., The phytochemical bergenin as an adjunct immunotherapy for tuberculosis in mice. J Biol Chem. 2019; 294(21): 8555-8563.
How to Cite
This work is licensed under a Creative Commons Attribution 4.0 International License.