Analysis of interaction mechanisms between main objects of tuberculosis-target therapy and corresponding selective inhibitors

  • D. O. Samofalova Institute of Food Biotechnology and Genomics, National Academy of Sciences of Ukraine
  • O. V. Rayevsky Institute of Food Biotechnology and Genomics, National Academy of Sciences of Ukraine
  • S. P. Ozheredov Institute of Food Biotechnology and Genomics, National Academy of Sciences of Ukraine
  • S. I. Spivak Institute of Food Biotechnology and Genomics, National Academy of Sciences of Ukraine
  • М. М. Stykhylias Institute of High Technologies of Taras Shevchenko National University of Kyiv
  • D. S. Ozheredov Institute of Food Biotechnology and Genomics, National Academy of Sciences of Ukraine
  • P. A. Karpov Institute of Food Biotechnology and Genomics, National Academy of Sciences of Ukraine
DOI: https://doi.org/10.7124/FEEO.v28.1390

Abstract

Aim. Search for new inhibitors of the mitotic apparatus of mycobacterium and a number of enzymatic targets. Methods. 3D models of key targets reconstruction and geometry optimization and analysis of biologically active conformations of inhibitors were performed according to a previously developed technique. Results. A revision of mycobacterial inhibitors, which exhibit antimicrobial action against representatives of the genus Mycobacterium, was carried out, which made it possible to create an appropriate reference library of compounds. The complete spatial structure of a number of the main targets of targeted therapy for tuberculosis was reconstructed and verified, and the features of their interaction with selective inhibitors were established. Chemogenomic profiling was performed, which made it possible to draw conclusions regarding the uniqueness of the studied sites and the potential toxicity of compounds related to these sites for humans. Conclusions. A well-developed search algorithm for known inhibitors of proteins with M. tuberculosis allows further study of the features of their interaction with the corresponding homologues of M. bovis and the development of new, more selective compounds using molecular dynamics and docking methods.

Keywords: tuberculosis, in silico, anti-tuberculosis drugs.

References

Cruz-Knight W., Blake-Gumbs L. Tuberculosis: an overview. Prim Care. 2013. Vol. 40 (3). P. 743–756. doi: 10.1016/j.pop.2013.06.003.

Riojas M.A., McGough K.J., Rider-Riojas C.J., Rastogi N., Hazbón M.H. Phylogenomic analysis of the species of the Mycobacterium tuberculosis complex demonstrates that Mycobacterium africanum, Mycobacterium bovis, Mycobacterium caprae, Mycobacterium microti and Mycobacterium pinnipedii are later heterotypic synonyms of Mycobacterium tuberculo-sis. Int J Syst Evol Microbiol. 2018. Vol. 68 (1). P. 324–332. doi: 10.1099/ijsem.0.002507.

Pai M., Behr M., Dowdy D. Tuberculosis. Nat Rev Dis Primers. 2016. Vol. 2. P. 16076. doi: 10.1038/nrdp.2016.76.

Feshchenko Yu. I. Suchasni tendentsii vyvchennia problem tuberkul'ozu. Ukrains'kyy pul'monolohichnyy zhurnal. 2019. No 1. P. 8–24.

Raviglione M., Uplekar M., Weil D., Kasaeva T. Tuberculosis makes it onto the international political agenda for health… finally. Lancet Glob Health. 2018. Vol. 6 (1). P. e20–e21. doi: 10.1016/S2214-109X(17)30449-7.

Macalino S.J.Y., Billones J.B., Organo V.G., Carrillo M.C.O. In silico strategies in tuberculosis drug discovery. Molecules. 2020. Vol. 25 (3). P. 665. doi: 10.3390/molecules25030665.

Fofana M.O., Dowdy D.W. Reply to anthony protecting pyrazinamide, a priority for improving outcomes in multidrug-resistant tuberculosis treatment. Antimicrob Agents Chemother. 2017. Vol. 61 (6). P. e00427–17. doi: 10.1128/AAC.00427-17.

Falzon D., Jaramillo E., Gilpin C., Weyer K. The role of novel approaches and new findings in the pharmacology of tuber-culosis medicines in improving treatment outcomes. Clin Infect Dis. 2018. Vol. 67 (suppl_3). P. S365–S367. doi: 10.1093/cid/ciy710.

Velásquez G.E., Becerra M.C., Gelmanova I.Y., Pasechnikov A.D., Yedilbayev A., Shin S.S., Andreev Y.G., Yanova G., Atwood S.S., Mitnick C.D., Franke M.F., Rich M.L., Keshavjee S. Improving outcomes for multidrug-resistant tuberculosis: aggressive regimens prevent treatment failure and death. Clin Infect Dis. 2014. Vol. 59 (1). P. 9–15. doi: 10.1093/cid/ciu209.

Zwolska Z. Improving treatment outcomes for tuberculosis. J Bioequiv Availab. 2017. Vol. 9 (4). P. 442–446. doi: 10.4172/jbb.1000341.

Conde M.B., Mello F.C., Duarte R.S. A phase 2 randomized trial of a rifapentine plus moxifloxacin-based regimen for treatment of pulmonary tuberculosis. PLoS One. 2016. Vol. 11 (5). P. e0154778. doi: 10.1371/journal.pone.0154778.

Saukkonen J.J., Cohn D.L., Jasmer R.M., Schenker S., Jereb J.A., Nolan C.M., Peloquin C.A., Gordin F.M., Nunes D., Strader D.B., Bernardo J., Venkataramanan R., Sterling T.R. ATS (American Thoracic Society) hepatotoxicity of antituberculosis therapy subcommittee. an official ats statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006. Vol. 174 (8). P. 935–952. doi: 10.1164/rccm.200510-1666ST.

World Health Organization (WHO) guidelines on the management of latent tuberculosis infection. Geneva, Switzerland: World Health Organization (WHO), 2019.

Karpov P.A., Brytsun V.M., Raievskyi O.V., Demchuk O.M., Pydiura M.O., Ozheriedov S.P., Samofalova D.O., Spivak S.I., Yemets A.I., Kalchenko V.I., Blium Ya.B. Vysokopropusknyi skryninh rechovyn z antymitotychnoiu aktyvnistiu na bazi virtualnoi orhanizatsii CSLabGrid. Nauka ta innovatsii. 2015. Vol. 11 (1). P. 92–100.

Karpov P.A., Demchuk O.M., Britsun V.M., Lytvyn D.I., Pydiura M.O., Rayevsky O.V., Samofalova D.O., Spivak S.I., Volochnyuk D.M., Yemets A.I., Blume Ya.B. New imidazole inhibitors of Mycobacterial FtsZ: the way from high-throughput molecular screening in Grid up to in vitro verification. Nauka innov. 2016. Vol. 12 (3). P. 44–59.