innosferaНаука и инновацииScience and Innovations1818-98572412-9372Издательский дом «Белорусская наука»10.29235/1818-9857-2026-03-78-83innosfera-1009Research ArticleДИССЕРТАЦИОННЫЕ ИССЛЕДОВАНИЯDISSERTATION RESEARCHКомпьютерная идентификация молекул-кандидатов в лекарственные препараты против туберкулезаComputer-aided identification of candidate molecules for tuberculosis drugsГончарА.GoncharA.

Анна Гончар, младший научный сотрудник

Anna Gonchar

hanna.hanchar@gmail.comФурсК.FursK.

Константин Фурс, младший научный сотрудник

Konstantin Furs

ТузиковА.TuzikovA.

Александр Тузиков, заведующий лабораторией математической кибернетики ОИПИ НАН Беларуси, член-корреспондент

Alexander Tuzikov

АндриановА.AndrianovA.

Александр Андрианов, главный научный сотрудник Института биоорганической химии НАН Беларуси, доктор химических наук, профессор

Alexander Andrianov

Объединенный институт проблем информатики НАН БеларусиBelarusИнститут биоорганической химии НАН БеларусиBelarus202617042026037883Copyright © Издательский дом «Белорусская наука», 20262026Издательский дом «Белорусская наука»Издательский дом «Белорусская наука»https://innosfera.belnauka.by/jour/about/submissions#copyrightNoticehttps://innosfera.belnauka.by/jour/article/view/1009

Проведен виртуальный скрининг библиотеки биологически активных соединений, направленный на идентификацию малых молекул, способных ингибировать каталитическую активность еноил-ацил-переносящий белокредуктазы (InhA) микобактерии туберкулеза (МБТ) – одного из ключевых ферментов, участвующих в биосинтезе миколовых кислот клеточной стенки МБТ. С этой целью использован комплексный вычислительный подход к перепрофилированию лекарств, включающий высокопроизводительный докинг фермента InhA с соединениями из молекулярной библиотеки, содержащей одобренные FDA препараты и исследуемые кандидаты в лекарственные средства, молекулярную динамику комплексов лиганд/InhA-NAD+, отбор наиболее перспективных соединений и экспериментальное определение их минимальной ингибирующей концентрации МИК90. В результате обнаружено соединение-лидер, которое показало значение МИК90, равное 62,5 мкМ, против вакцинного штамма Mycobacterium bovis BCG и МБТ, что позволяет рассматривать его в качестве базовой структуры для разработки новых противотуберкулезных молекул.

Structure-based virtual screening of the library of bioactive compounds was used to identify novel small-molecule compounds that can inhibit the catalytic activity of Mycobacterium tuberculosis (Mtb) enoyl acyl carrier protein reductase (InhA), one of the key enzymes involved in the biosynthesis of mycolic acids of the Mtb cell wall. To do this, we employed an integrated computational approach to drug repurposing which included high-throughput docking of the InhA enzyme with small-molecule compounds from the library of bioactive molecules containing the FDA-approved drugs and investigational drug candidates, molecular dynamics simulations of the ligand/InhA-NAD+ complexes, binding free energy calculations, post-modeling analysis followed by selection of the most promising drug candidates and experimental determination of their minimum inhibitory concentration MIC90. As a result, a lead compound which showed the MIC90 value of 62.5 µM against the vaccine strain Mycobacterium bovis and Mtb was found, giving hope that this compound forms a promising scaffold for the development of novel antitubercular molecules of clinical significance with activity against an important target of Mtb.

микобактерия туберкулезавиртуальный скринингперепрофилирование лекарствингибиторыфермент InhAпротивотуберкулезные препаратыMycobacterium tuberculosisvirtual screeningdrug repurposinginhibitorsenzyme InhAantituberculosis drugsРабота выполнена при поддержке грантов Белорусского республиканского фонда фундаментальных исследований (Ф24КИТГ-016), Международного научно-технического центра (МНТЦ, проект PR150) и Консорциума и портала программы «Лекарственно-устойчивый туберкулез».ReferencesWHO. Global tuberculosis report 2024 / World Health Organization, 2024 // https://www.who.int/teams/global-programme-on-tuberculosis-and-lunghealth/tb-reports/global-tuberculosis-report-2024.WHO. Global tuberculosis report 2024 / World Health Organization, 2024 // https://www.who.int/teams/global-programme-on-tuberculosis-and-lunghealth/tb-reports/global-tuberculosis-report-2024.Shetye G.S. New tuberculosis drug targets, their inhibitors, and potential therapeutic impact / G.S. Shetye, S.G. Franzvlau, S. Cho // Transl. Res. 2020. Vol. 220. P. 68–97. Doi.org/10.1016/j.trsl.2020.03.007.Shetye G.S. New tuberculosis drug targets, their inhibitors, and potential therapeutic impact / G.S. Shetye, S.G. Franzvlau, S. Cho // Transl. Res. 2020. Vol. 220. P. 68–97. Doi.org/10.1016/j.trsl.2020.03.007.North E.J. New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics / E.J. North, M. Jackson, R.E. Lee // Curr. Pharm. Des. 2014. Vol. 20(27). P. 4357–4378.North E.J. New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics / E.J. North, M. Jackson, R.E. Lee // Curr. Pharm. Des. 2014. Vol. 20(27). P. 4357–4378.Pawełczyk J. The molecular genetics of mycolic acid biosynthesis / J. Pawełczyk, L. Kremer // Microbiol. Spect. 2014. Vol. 2(4). MGM2-0003-2013.Pawełczyk J. The molecular genetics of mycolic acid biosynthesis / J. Pawełczyk, L. Kremer // Microbiol. Spect. 2014. Vol. 2(4). MGM2-0003-2013.Conditional depletion of KasA, a key enzyme of mycolic acid biosynthesis, leads to mycobacterial cell lysis / A. Bhatt [et al.] // J. Bacteriol. 2005. Vol. 187. P. 7596–7606.Conditional depletion of KasA, a key enzyme of mycolic acid biosynthesis, leads to mycobacterial cell lysis / A. Bhatt [et al.] // J. Bacteriol. 2005. Vol. 187. P. 7596–7606.Duan X. Crucial components of mycobacterium type II fatty acid biosynthesis (Fas-II) and their inhibitors / X. Duan, X. Xiang, J. Xie // FEMS Microbiol. Lett. 2014. Vol. 360 (2). P. 87–99. Https://doi.org/10.1111/1574-6968.12597.Duan X. Crucial components of mycobacterium type II fatty acid biosynthesis (Fas-II) and their inhibitors / X. Duan, X. Xiang, J. Xie // FEMS Microbiol. Lett. 2014. Vol. 360 (2). P. 87–99. Https://doi.org/10.1111/1574-6968.12597.Prasad S. Mycobacterium enoyl acyl carrier protein reductase (InhA): A key target for antitubercular drug discovery / S. Prasad, R.P. Bhole, P.B. Khedekar, R.V. Chikhale / Bioorg Chem. 2021. Vol. 115: 105242. Https://doi.org/10.1016/j.bioorg.2021.105242.Prasad S. Mycobacterium enoyl acyl carrier protein reductase (InhA): A key target for antitubercular drug discovery / S. Prasad, R.P. Bhole, P.B. Khedekar, R.V. Chikhale / Bioorg Chem. 2021. Vol. 115: 105242. Https://doi.org/10.1016/j.bioorg.2021.105242.Kruh N. Probing mechanisms of resistance to the tuberculosis drug isoniazid: conformational changes caused by inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis / N. Kruh, R. Rawat, B.P. Ruzsicska, P.J. Tonge // Prot. Sci. 2007. Vol. 16. P. 1617–1627.Kruh N. Probing mechanisms of resistance to the tuberculosis drug isoniazid: conformational changes caused by inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis / N. Kruh, R. Rawat, B.P. Ruzsicska, P.J. Tonge // Prot. Sci. 2007. Vol. 16. P. 1617–1627.Rawat R. The isoniazid-NAD adduct is a slow, tightbinding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: Adduct affinity and drug resistance / R. Rawat, A. Whitty, P.J. Tonge // Proc. Natl. Acad. Sci. USA. 2003. Vol. 100. P. 13881– 13886. Https://doi.org/10.1073/pnas.2235848100.Rawat R. The isoniazid-NAD adduct is a slow, tightbinding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: Adduct affinity and drug resistance / R. Rawat, A. Whitty, P.J. Tonge // Proc. Natl. Acad. Sci. USA. 2003. Vol. 100. P. 13881– 13886. Https://doi.org/10.1073/pnas.2235848100.Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid / C. Vilchèze [et al.] // Nat. Med. 2006. Vol. 12. P. 1027–1029. Https://doi.org/10.1038/nm1466.Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid / C. Vilchèze [et al.] // Nat. Med. 2006. Vol. 12. P. 1027–1029. Https://doi.org/10.1038/nm1466.Pan P. Targeting InhA, the FASII enoyl-ACP reductase: SAR studies on novel inhibitor scaffolds / P. Pan, P.J. Tonge // Curr. Top. Med. Chem. 2012. Vol. 12. P. 672–693. Https://doi.org/10.2174/156802612799984535.Pan P. Targeting InhA, the FASII enoyl-ACP reductase: SAR studies on novel inhibitor scaffolds / P. Pan, P.J. Tonge // Curr. Top. Med. Chem. 2012. Vol. 12. P. 672–693. Https://doi.org/10.2174/156802612799984535.DrugBank 5.0: a major update to the DrugBank database for 2018 / D.S. Wishart [et al.] // Nucl. Acids Res. 2017. Vol. 46. P. D1074–D1082. Https://doi.org/10.1093/nar/gkx1037.DrugBank 5.0: a major update to the DrugBank database for 2018 / D.S. Wishart [et al.] // Nucl. Acids Res. 2017. Vol. 46. P. D1074–D1082. Https://doi.org/10.1093/nar/gkx1037.Sterling T. ZINC 15 – Ligand discovery for everyone / T. Sterling, J.J. Irwin // J. Chem. Inf. Model. 2015. Vol. 55(11). P. 2324–2337. Https://doi.org/10.1021/acs.jcim.5b00559.Sterling T. ZINC 15 – Ligand discovery for everyone / T. Sterling, J.J. Irwin // J. Chem. Inf. Model. 2015. Vol. 55(11). P. 2324–2337. Https://doi.org/10.1021/acs.jcim.5b00559.Trott O. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading / O. Trott, A.J. Olson // J. Comp. Chem. 2010. Vol. 31. P. 455–461. Https://doi.org/10.1002/jcc.21334.Trott O. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading / O. Trott, A.J. Olson // J. Comp. Chem. 2010. Vol. 31. P. 455–461. Https://doi.org/10.1002/jcc.21334.Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis / X. He [et al.] // J. Med. Chem. 2006. Vol. 49(21). P. 6308–6323. Https: // doi: 10.1021/jm060715y.Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis / X. He [et al.] // J. Med. Chem. 2006. Vol. 49(21). P. 6308–6323. Https: // doi: 10.1021/jm060715y.Wójcikowski M. Performance of machine-learning scoring functions in structure-based virtual screening / M. Wójcikowski, P. Ballester, P. Siedlecki // Sci. Rep. 2017. Vol. 7. P. 46710. Https://doi.org/10.1038/srep46710.Wójcikowski M. Performance of machine-learning scoring functions in structure-based virtual screening / M. Wójcikowski, P. Ballester, P. Siedlecki // Sci. Rep. 2017. Vol. 7. P. 46710. Https://doi.org/10.1038/srep46710.Durrant J.D. NNScore 2.0: A neural-network receptor–ligand scoring function / J.D. Durrant, J.A. McCammon // J. Chem. Inf. Model. 2011. Vol. 51(11). P. 2897–2903. Https://doi.org/10.1021/ci2003889.Durrant J.D. NNScore 2.0: A neural-network receptor–ligand scoring function / J.D. Durrant, J.A. McCammon // J. Chem. Inf. Model. 2011. Vol. 51(11). P. 2897–2903. Https://doi.org/10.1021/ci2003889.Palacio-Rodríguez K. Exponential consensus ranking improves the outcome in docking and receptor ensemble docking / K. Palacio-Rodríguez, I. Lans, C.N. Cavasotto, P. Cossio // Sci. Rep. 2019. Vol. 9(1). Article No. 5142. Https://doi.org/10.1038/s41598-019-41594-3.Palacio-Rodríguez K. Exponential consensus ranking improves the outcome in docking and receptor ensemble docking / K. Palacio-Rodríguez, I. Lans, C.N. Cavasotto, P. Cossio // Sci. Rep. 2019. Vol. 9(1). Article No. 5142. Https://doi.org/10.1038/s41598-019-41594-3.AMBER 2018 / D.A. Case [et al.] // University of California, 2018.AMBER 2018 / D.A. Case [et al.] // University of California, 2018.Comparison of simple potential functions for simulating liquid water / W.L. Jorgensen [et al.] // J. Chem. Phys. 1983. Vol. 79 (2). P. 926–935. Https://doi.org/10.1063/1.445869.Comparison of simple potential functions for simulating liquid water / W.L. Jorgensen [et al.] // J. Chem. Phys. 1983. Vol. 79 (2). P. 926–935. Https://doi.org/10.1063/1.445869.Ryckaert J.P. Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes / J.P. Ryckaert, G. Ciccotti, H.J.C. Berendsen // J. Comput. Phys. 1977. Vol. 23 (3). P. 327–341. Https://doi.org/10.1016/0021-9991(77)90098-5.Ryckaert J.P. Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes / J.P. Ryckaert, G. Ciccotti, H.J.C. Berendsen // J. Comput. Phys. 1977. Vol. 23 (3). P. 327–341. Https://doi.org/10.1016/0021-9991(77)90098-5.A smooth particle mesh Ewald method / U. Essmann [et al.] // J. Chem. Phys. 1995. Vol. 103. P. 8577–8593. Https://doi.org/10.1063/1.470117.A smooth particle mesh Ewald method / U. Essmann [et al.] // J. Chem. Phys. 1995. Vol. 103. P. 8577–8593. Https://doi.org/10.1063/1.470117.Genheden S. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinity / S. Genheden, U. Ryde // Expert Opin. Drug Discov. 2015. Vol. 10(5). P. 449–461. Https://doi.org/10.1517/17460441.2015.1032936.Genheden S. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinity / S. Genheden, U. Ryde // Expert Opin. Drug Discov. 2015. Vol. 10(5). P. 449–461. Https://doi.org/10.1517/17460441.2015.1032936.Targeting tuberculosis and malaria through inhibition of enoyl reductase / M.R. Kuo [et al.] // J. Biol. Chem. 2003. Vol. 278(23). P. 20851–20859. Https://doi.org/10.1074/jbc.m211968200.Targeting tuberculosis and malaria through inhibition of enoyl reductase / M.R. Kuo [et al.] // J. Biol. Chem. 2003. Vol. 278(23). P. 20851–20859. Https://doi.org/10.1074/jbc.m211968200.

The authors declare that there are no conflicts of interest present.