Docking for a novel class of tryptanthrin analogues against inhibitors of mycobacterium tuberculosis
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MACAEV, Fliur; DUCA, Gheorghe. Docking for a novel class of tryptanthrin analogues against inhibitors of mycobacterium tuberculosis. In: NANO-2016: Ethical, Ecological and Social Problems of Nanoscience and Nanotechnologies. 11-14 mai 2016, Chişinău. Chișinău, Republica Moldova: 2016, pp. 33-35.
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NANO-2016: Ethical, Ecological and Social Problems of Nanoscience and Nanotechnologies 2016
Conferința "NANO-2016: Ethical, Ecological and Social Problems of Nanoscience and Nanotechnologies"
2016, Chişinău, Moldova, 11-14 mai 2016

Docking for a novel class of tryptanthrin analogues against inhibitors of mycobacterium tuberculosis


Pag. 33-35

Macaev Fliur, Duca Gheorghe
 
Institute of Chemistry
 
Disponibil în IBN: 28 aprilie 2020


Rezumat

Tuberculosis (TB) is a bacterial infection caused by Mycobacterium tuberculosis that has affected one third of global population. In 2013, around 9 mln people became infected with TB, and 1.5 mln died from this disease, of which 360000 were HIV co-infected [Global report, 2014]. Emergence and wide spread of multidrug resistant tuberculosis (MDR-TB) along with extensively resistant tuberculosis (XDR-TB) aggravate the problem, since few new medicines and therapeutic schemes have been approved to combat the resistant forms. Eastern European and central Asian countries have the highest levels of MDR-TB, reaching 35% of new cases and 75% of previously treated cases in some settings [Global report, 2014]. Therefore, there is a constantly growing demand in new highly active and effective therapeutics to combat TB and its resistant form.figureTryptanthrin Tryptanthrin (TRPN) is a naturally occurring compound from the class of tryptophanderived alkaloids produced by different plants (Couroupita guianensis, Isatis tinctoria, Polygonum tinctorium, Strobilanthes cusia, Wrightia tinctoria) and fungi (Candida lypolitica). Antimycobacterial activity of TRPN and its derivatives was for the first time reported [Baker, W. R., & Mitscher, L. A. (1995). U.S. Patent No. 5,441,955]. The study identified two most promising compounds with high in vitro activity against MDR-TB strains, which, nevertheless, showed little efficiency in vivo. Later [Tripathi, A., Wadia, N., Bindal, D., Jana, T. Indian J. Biochem. Biophys. 2012, 49 (6), 435-441] performed molecular docking analysis of TRPN and its analogues with enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis. The study showed good affinity between the alkaloid and its two analogues to the ENR binding site with free binding energy of -7.94 kcal/mol and inhibition constant (Ki) of 1.50 μm. Hwang et al [Hwang, J. M., Oh, T., Kaneko, T., Upton, A. M., Franzblau, S. G., Ma, Z., ... & Kim, P. Journal of natural products. 2013, 76(3), 354-367] have also performed a study of multiple TRPN analogues that resulted in determination of two compounds with highest activity in studies in vitro and improved bioavailability in vivo as compared to TRPN, which, however, did not demonstrate efficacy in acute murine tuberculosis following 4 weeks administration in doses of 400 mg/kg. Interestingly, TRPN was found to be able to reverse the drug resistance towards certain anticancer agents in breast cancer cell lines. Another important set of TRPNs’ activities are immune-modulator effects: down-regulation of interleukin-4 production by Th2 cells, inhibition of nitric oxide and prostaglandin E2 synthesis in macrophages, inhibition of interferon-γ and interleukin-2 production by mouse spleen cells and Peyer’s patch (PP) lymphocytes in vitro, inhibition of indole amine 2,3-dioxygenase, significant reduction in the levels of TSLP, IL-4, IFN-γ, IL-6, TNF-α, chemokine, and caspase-1 in atopic dermatitis (AD) skin lesions, suppression of the histidine decarboxylase levels with consequent reduction of histamine levels in AD model. TRPN and its derivatives were proposed as immunotherapeutic agent to treat cancer, either alone or in combination with other anti-cancer therapies (e.g. chemo therapeutic agents, mAbs or other immune modulators), as well as for the treatment of BCG, cholera, plague, typhoid, hepatitis B infection, influenza, inactivated polio, rabies, measles, mumps, rubella, oral polio, SARS, yellow fever, tetanus, diphtheria, hemophilus influenzae B, meningococcus infection, and pneumococcus infection. Let us consider the affinity and interaction of the synthesized inhibitors against InhA of Mycobacterium tuberculosis Mtb. Earlier analogues of natural alkaloids of TRPN, which have anti-tubercular activity against MDR-TB (multi-drug resistant tuberculosis), were in silico investigated by molecular docking. Results show that TRPN and its analogues have exhibited good affinity to the binding site of InhA (ENR), and free energy binding to active site of InhA is changing in the limits of -6.44  -7.75 kcal mol-1. Inhibition constant is changing between 2.07 and 19.15 μm. As a continuation of the researches on docking, we have studied the ligand-receptor interaction of the compounds synthesized with the binding site of InhA. 3D-crystallographic structure of the target protein InhA was retrieved through Brookhaven PDB under the accession code 4U0J. The resulting values of docking energy and stabilization energy are given in Table X . As it is seen from the data in the table, binding affinity changes in the limits of -5.5 and 9.4 kcal mol-1. The range of the stabilization energy (E2) changes is wide enough and equals to 1.5  6.9 kcal mol-1.figureactivities are immune-modulator effects: down-regulation of interleukin-4 production by Th2 cells, inhibition of nitric oxide and prostaglandin E2 synthesis in macrophages, inhibition of interferon-γ and interleukin-2 production by mouse spleen cells and Peyer’s patch (PP) lymphocytes in vitro, inhibition of indole amine 2,3-dioxygenase, significant reduction in the levels of TSLP, IL-4, IFN-γ, IL-6, TNF-α, chemokine, and caspase-1 in atopic dermatitis (AD) skin lesions, suppression of the histidine decarboxylase levels with consequent reduction of histamine levels in AD model. TRPN and its derivatives were proposed as immunotherapeutic agent to treat cancer, either alone or in combination with other anti-cancer therapies (e.g. chemo therapeutic agents, mAbs or other immune modulators), as well as for the treatment of BCG, cholera, plague, typhoid, hepatitis B infection, influenza, inactivated polio, rabies, measles, mumps, rubella, oral polio, SARS, yellow fever, tetanus, diphtheria, hemophilus influenzae B, meningococcus infection, and pneumococcus infection. Let us consider the affinity and interaction of the synthesized inhibitors against InhA of Mycobacterium tuberculosis Mtb. Earlier analogues of natural alkaloids of TRPN, which have anti-tubercular activity against MDR-TB (multi-drug resistant tuberculosis), were in silico investigated by molecular docking. Results show that TRPN and its analogues have exhibited good affinity to the binding site of InhA (ENR), and free energy binding to active site of InhA is changing in the limits of -6.44  -7.75 kcal mol-1. Inhibition constant is changing between 2.07 and 19.15 μm. As a continuation of the researches on docking, we have studied the ligand-receptor interaction of the compounds synthesized with the binding site of InhA. 3D-crystallographic structure of the target protein InhA was retrieved through Brookhaven PDB under the accession code 4U0J. The resulting values of docking energy and stabilization energy are given in Table X . As it is seen from the data in the table, binding affinity changes in the limits of -5.5 and 9.4 kcal mol-1. The range of the stabilization energy (E2) changes is wide enough and equals to 1.5  6.9 kcal mol-1.figureFigure 2. A three-dimensional view of HOMO/LUMO orbitals for compound 1. Week hydrophobic interaction with Met199 (3.39Å), Gly96 (3.58Å) and Ile215 (3.59Å) happens in the case of compound 1. Inactive molecule 2 binds with receptor for the account of aromatic--aromatic moiety (Gly96-3.34Å) and H--Aromatic interaction with Phe97 (3.71Å), Met98 (3.33 Å) and Tyr158 (3.56Å).figureFigure 3. A three-dimensional view of HOMO/LUMO orbitals for compound 2. The discussion of the electron density distribution in the active centre of InhA (as in the case of IDO-1) is important for the understanding of the mechanism of inhibition related to the synthesized molecules. A special interest for the ligand-receptor interaction presents analysis of the border orbitals (HOMO-LUMO). Electron density distribution on these orbitals for the molecules 1 and 2 is given in Fig.2 as well as in Fig.3. As seen from Fig.2, electron density for the compound 1 is distributed both on ligand and amino acid residues that causes more effective donor-acceptor interaction. For the compound 2 (Fig.3), electron density is concentrated on residues and absent on the ligand’s atoms. The E(2) value for the compound 1 is 5.7 kcal mol-1, while for the compound 2 it equals to 2.1 kcal mol-1. It should be noted that opposite to the mechanism of IDO-1 inhibition, there is no good correlation dependency between anti-tuberculosis activity and such parameters as binding affinity and stabilization energy E(2) for the second mechanism of the InhA inhibition.