A Systematic Bioinformatics Approach for Multiple Virtual Screening for Finding Novel MDR-TB Antagonists: Structure Based Screens & Toxicity Prediction Analyzing Poly Pharmacological Affects

Authors

  • V L Saxena Coordinator, Bioinformatics Infrastructure Facilities Centre of DBT, D.G.(P.G.) College, Civil lines, Kanpur, India Author
  • G Yadav Research Scholar, Dept. of Zoology, D.G.(P.G.) College, Civil lines, Kanpur, India Author
  • A Chaudhuri Bioinformatics Infrastructure Facilities Centre of DBT, D.G.(P.G.) College, Civil lines, Kanpur, India, Author

Keywords:

Drug resistant, tumorigenic properties, pharmacological optimization

Abstract

Multidrug-resistant tuberculosis has been
resistant over more than two primary drugs (isoniazid
and rifampin) resulted due to misuse and
mismanagement which leads to administration of
improper treatment regimens and failure to ensure that
patients complete the whole course of treatment.
Screening the library of MDR-TB antagonists against
the bacterial strains can improve the pharmacological
optimization compared over the primary drugs.
In the present study, virtual screening has been
introduced using surflex dock targeting mycobacterial
metabolite (DNA Gyrase) virtually screened against
chemical library of Rifampin and Isoniazid.
Consequently, HtrA2 has been virtually screened
against chemical library of ciprofloxacin, ofloxacin and
moxifloxacin according to their bio affinity and
analysed polypharmacological affects.
Derivate of Ofloxacin (ZINCID_39383034) demonstrate
better interactions with HtrA2 (PDBID_2PZD) and so
on derivate of Rifampin (ZINC_ID85907485)
demonstrate better interactions with DNA Gyrase
(PDBID_3IFZ) following Lipinski’s rule of five and
without any mutagenic, toxic or carcinogenic effects.
Comparatively, analysing the binding patterns of
derivates contrary to their primary drugs, inferred that
docking score of the derivates have been significant
than the primary drug and toxic level has been reduced
in contrary to their primary drugs which has proved
hints for the future design of new derivatives with
higher potency and specificity.

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References

Espinal MA, Kim SJ, Suarez PG, Kam KM, Khomenko AG (2000). Standard short-course chemotherapy for drug-resistant tuberculosis:Treatment outcomes in 6 countries. JAMA 283: 2537-2545.

Cobelens FGJ, Heldal E, Kimerling ME, Mitnick CD, Podewils LJ (2008).Scaling up programmatic management of drug-resistant tuberculosis: A prioritized research agenda. PLoS Med 5(7):50.

Singhal (2012). Analysis of intracellular expressed proteins of Mycobacterium tuberculosis clinical isolates. Proteome Science14.

Ginsberg AM(2010). Drugs in development for tuberculosis. Drugs 70:2201-2214.

Barroso E., Mota RMS, Santos RO, Sousa ALO, Barroso JB, Rodrigues JLN (2003). Risk factors for acquired multidrug-resistant tuberculosis. J Pneumol 29(2):89-97

Iseman MD(1993). Treatment of multidrug-resistant tuberculosis. New England Journal of Medicine 329:784-791.

Espinal M.A., Kim S.J., Suarez P.G., Kam K.M., Khomenko A.G., Migliori G.B. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcome in six countries. JAMA. 2000, 283:2537-2545.

Chaulet P, Raviglione M, Bustreo F(1996). Epidemiology, control and treatment of multidrug-resistant tuberculosis. Drugs 52 Suppl 2:103-108.

Zhang Y, Heym B, Allen B (1992). The catalase-peroxidase gene and isoniazid resistance in M.tuberculosis. Nature 358:591–593.

Piatek AS, Telenti A, Murray MR(2000). Genetotypic analysis of Mycobacterium tuberculosis in two distinct populations using molecular beacons: implications for rapid susceptibility testing. Antimicob Agents Chemother 44:103–10.

Telenti A, Imboden P, Marchesi F (1993).Detection of rifampicin resistance mutations in Mycobacterium tuberculosis. Lancet 341: 647–650.

Singla(2011). A web server for predicting inhibitors against bacterial target GlmU protein. BMC Pharmacology 11 :(5).

Keshavjee S, Farmer PE(2012). Tuberculosis, drug resistance, and the history of modern medicine. N Engl J Med. 367: 931-936.

Madhusudan K, Ramesh V, Nagaraja V(1994). GyraseMolecular cloning of gyrA and gyrB genes of Mycobacterium tuberculosis: analysis of nucleotide sequence. Gyrase Biochem. Mol. Biol. Int 33(4): 651-660.

Gowsia D, Babajan B, Chaitanya M, Rajasekhar C, Madhusudana P,Anuradha CM, Ramakrishna G, Sambasiva Rao KRS and Kumar CS(2009). In silico effective inhibition of galtifloxacin on built Mtb-DNA gyrase. Journal of Bioinformatics and Sequence Analysis 1(4):50-55.

Li W, Srinivasula SM, Chai J, Li P, Wu JW, Zhang Z(2002). Structural insights into the proapoptotic function of mitochondrial serine protease HtrA2/Omi. Nat Struct Biol 9:436–441.

Fitzgerald JC, Camprubi MD, Dunn L, Wu HC, Ip NY, Kruger R, Martins LM, Wood1 NW and Plun-Favreau*1 H(2012).Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function Cell Death and Differentiation 19: 257–266.

Srinivasula SM, Gupta S, Datta P, Zhang ZJ, Hegde R, Cheong NE, Alnemri TF and Alnemri ES(2003). Inhibitor of Apoptosis Proteins are substrates for the Mitochondrial Serine Protease Omi/HtrA2. J. Biol. Chem 278:31469-31472.

Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L(2002). Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein–caspase interaction. J Biol Chem 277: 432–438.

Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R(2001). A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 8: 613–621.

Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM(2002). HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem 277: 445–454.

Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK(1998). Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19(14): 1639-1662.

Schuttelkopf AW, Van Aalten DM(2004). PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr., Sect. D: Biol. Crystallogr 60(8): 1355-1363.

Khan MM, Khan M., Alves MS, Sherwani SK, Baig MA and Kamal M(2013). Structure based assessment of rpoB gene from multiple-drug resistant Mycobacterium tuberculosis clinical isolate. International Journal of Advanced Research 1(7): 567-575

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Published

2017-11-02

Issue

Vol. 5 No. 6 (2017): International Journal of Innovative Research in Computer Science & Technology(NOV)2017

Section

Articles

How to Cite

A Systematic Bioinformatics Approach for Multiple Virtual Screening for Finding Novel MDR-TB Antagonists: Structure Based Screens & Toxicity Prediction Analyzing Poly Pharmacological Affects. (2017). International Journal of Innovative Research in Computer Science & Technology, 5(6), 381–389. Retrieved from https://acspublisher.com/journals/index.php/ijircst/article/view/13443