danДоклады Национальной академии наук БеларусиDoklady of the National Academy of Sciences of Belarus1561-83232524-2431The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1561-8323-2025-69-2-117-128dan-1243Research ArticleХИМИЯCHEMISTRYВиртуальный скрининг и ADMET-анализ в идентификации новых ингибиторов 17,20-лиазы человека (CYP17A1)Virtual screening and ADMET analysis in identification of new human 17,20-lyase (CYP17A1) inhibitorsШаладоноваМ. И.ShaladonovaM. I.

Шаладонова Марина Игоревна – аспирант, мл. науч. сотрудник

ул. Купревича, 5/2, 220084, Минск

Shaladonova Marina I. – Postgraduate Student, Junior Reseacher

5/2, Kuprevich Str., 220084, Minsk

m.shaladonova@gmail.comУсановС. А.UsanovS. A.

Усанов Сергей Александрович – член-корреспондент, д-р хим. наук, профессор

ул. Купревича, 5/2, 220084, Минск

Usanov Sergei A. – Corresponding Member, D. Sc. (Chemistry), Professor

5/2, Kuprevich Str., 220084, Minsk

usanov@iboch.byИнститут биоорганической химии Национальной академии наук БеларусиInstitute of Bioorganic Chemistry of the National Academy of Sciences of Belarus202506052025692117128Copyright © Шаладонова М.И., Усанов С.А., 20252025Шаладонова М.И., Усанов С.А.Shaladonova M.I., Usanov S.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://doklady.belnauka.by/jour/article/view/1243

С применением фармакофорного моделирования на основе структуры лиганда осуществлен виртуальный скрининг потенциальных ингибиторов 17,20-лиазной активности фермента CYP17A1 человека, вовлеченного в патогенез развития рака предстательной железы. При отборе соединений-лидеров оценивали их фармакокинетические параметры (ADMET) для снижения риска побочных эффектов на организм. В результате проведенных исследований идентифицировано 5 соединений, характеризующихся синтетической доступностью, приемлемыми фармакокинетическими параметрами. Согласно расчетным данным гибкого молекулярного докинга, найденные соединения имеют низкие значения свободной энергии связывания с каталитическим центром фермента, которые сопо ставимы с экспериментальным значением применяемого в клинической практике ингибитора CYP17A1 – абиратерона. Установлено, что связывание идентифицированных соединений с ферментом обусловлено ван-дер-ваальсовыми, липофильными, электростатическими и межмолекулярными водородными взаимодействиями с аминокислотными остатками активного центра и π-стэкингом с гем-группой фермента. Полученные результаты будут использованы для разработки новых противоопухолевых препаратов с минимальными побочными эффектами для лечения рака простаты, терапевтическое действие которых основано на ингибировании 17,20-лиазной активности CYP17A1.

The article describes the development of a robust pharmacophore model and pharmacophore screening of poten tial inhibitors of the 17,20-lyase activity of the human CYP17A1 enzyme – an important target in the treatment of prostate cancer. To choose the compounds with the best pharmacokinetics parameters ADMET analysis was performed. According to the calculated data of flexible molecular docking, there were found five compounds with low free energies of binding to the catalytic center of the enzyme, which are comparable to the experimental value of the CYP17A1 inhibitor abiraterone used in clinical practice for treatment castration-resistant prostate cancer. It was established that the connection of the identified compounds with the enzyme is due to van der Waals, lipophilic, electrostatic and intermolecular hydrogen bonds with amino acid residues of the active center and π-stacking with the heme group of the enzyme. The results obtained will be used to develop new drugs with minor side effects for the treatment of prostate cancer due to inhibition of the 17,20-lyase activity of CYP17A1.

CYP17A1 человекарак предстательной железы1720-лиазная активность CYP17A1фармакофорное моделированиефармакофорный скринингфармакокинетические параметрыгибкий молекулярный докингhuman CYP17A1prostate cancer1720-lyase activity of CYP17A1pharmacophore modelingpharmacophore screeningpharmacokinetic parametersflexible molecular dockingReferencesNon-steroidal CYP17A1 Inhibitors: Discovery and Assessment / T. Wrobel, F. S. Jorgensen, A. V. Pandey [et al.] // Journal of Medicinal Chemistry. – 2023. – Vol. 66, N 10. – P. 6542–6566. https://doi.org/10.1021/acs.jmedchem.3c00442Wrobel T., Jorgensen F. S., Pandey A. V., Grudzinska A., Sharma K., Yakubu J., Bjorkling F. Non-steroidal CYP17A1 inhibitors: discovery and assessment. Journal of Medicinal Chemistry, 2023, vol. 66, no. 10, pp. 6542–6566. https://doi.org/10.1021/acs.jmedchem.3c00442Prospective computational design and in vitro bio-analytical tests of new chemical entities as potential selective CYP17A1 lyase inhibitors / N. J. Gumede, W. Nxumalo, K. Bisetty [et al.] // Bioorganic Chemistry. – 2020. – Vol. 94. – Art. 103462. https://doi.org/10.1016/j.bioorg.2019.103462Gumede N. J., Nxumalo W., Bisetty K., Gilabert L. E., Medina-Hernandez M. J., Sagrado S. Prospective computational design and in vitro bio-analytical tests of new chemical entities as potential selective CYP17A1 lyase inhibitors. Bioorganic Chemistry, 2020, vol. 94, art. 103462. https://doi.org/10.1016/j.bioorg.2019.103462Рак предстательной железы: лечение и диагностика // Республиканский научно-практический центр онкологии и медицинской радиологии имени Н. Н. Александрова. – URL: https://omr.by/lechenie-opukholej/urologicheskie-opukholi/rak-predstatelnoj-zhelezy (дата обращения: 11.06.2024).Prostate cancer: treatment and diagnosis. N. N. Alexandrov National Cancer Centre of Belarus. URL: https://omr.by/lechenie-opukholej/urologicheskie-opukholi/rak-predstatelnoj-zhelezy (accessed 11 June 2024) (in Russian).Bird, I. M. The hunt for a selective 17,20 lyase inhibitors: learning lessons from nature / I. M. Bird, D. H. Abbott // Journal of Steroid Biochemistry and Molecular Biology. – 2016. – Vol. 163. – P. 136–146. https://doi.org/10.1016/j.jsbmb.2016.04.021Bird I. M., Abbott D. H. The hunt for a selective 17,20 lyase inhibitors: learning lessons from nature. Journal of Steroid Biochemistry and Molecular Biology, 2016, vol. 163, pp. 136–146. https://doi.org/10.1016/j.jsbmb.2016.04.021Promising tools in prostate cancer research: selective non-steroidal cytochrome P450 17A1 inhibitors / S. Bonomo, C. H. Hansen, E. M. Petrunak [et al.] // Scientific Reports. – 2016. – Vol. 6. – Art. 29468. https://doi.org/10.1038/srep29468Bonomo S., Hansen C. H., Petrunak E. M., Scott E. E., Styrishave B., Jørgensen F. S., Olsen L. Promising tools in prostate cancer research: selective non-steroidal cytochrome P450 17A1 inhibitors. Scientific Reports, 2016, vol. 6, no. 1, art. 29468. https://doi.org/10.1038/srep29468Structural and functional evaluation of clinically relevant inhibitors of steroidogenic cytochrome P450 17A1 / E. M. Petrunak, S. A. Rogers, J. Aubé, E. E. Scott // Drug Metabolism and Disposition. – 2017. – Vol. 45, N 6. – P. 635–645. https://doi.org/10.1124/dmd.117.075317Petrunak E. M., Rogers S. A., Aubé J., Scott E. E. Structural and functional evaluation of clinically relevant inhibitors of steroidogenic cytochrome P450 17A1. Drug Metabolism and Disposition, 2017, vol. 45, no. 6, pp. 635–645. https://doi.org/10.1124/dmd.117.075317Диченко, Я. В. Компьютерное моделирование строения и реакционной способности молекул / Я. В. Диченко. – Минск, 2023. – 139 с.Dzichenka Y. V. Computer Modeling of the Structure and Reactivity of Molecules. Minsk, 2023. 139 p. (in Russian).Pharmacophore modeling and its applications / R. Tyagi, A. Singh, K. Chaudhary, M. Yadav // Bioinformatics. – 2022. – Vol. 1. – P. 269–289. https://doi.org/10.1016/B978-0-323-89775-4.00009-2Tyagi R., Singh A., Chaudhary K. K., Yadav M. Pharmacophore modeling and its applications. Bioinformatics, 2022, vol. 1, pp. 269–289. https://doi.org/10.1016/B978-0-323-89775-4.00009-2C-(17,20)-lyase inhibitors. Part 2: design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1Himidazoles as novel C-(17,20)-lyase inhibitors / N. Matsunaga, T. Kaku, A. Ojida [et al.] // Bioorganic and Medicinal Chemistry. – 2004. – Vol. 12, N 16. – P. 4313–4336. https://doi.org/10.1016/j.bmc.2004.06.016Matsunaga N., Kaku T., Ojida A., Tanaka T., Hara T., Yamaoka M., Kusaka M., Tasaka A. C(17,20)-lyase inhibitors. Part 2: design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C(17,20)-lyase inhibitors. Bioorganic and Medicinal Chemistry, 2004, vol. 12, no. 16, pp. 4313–4336. https://doi.org/10.1016/j.bmc.2004.06.01617,20-Lyase inhibitors. Part 4: Design, synthesis and structure-activity relationships of naphthylmethylimidazole derivatives as novel 17,20-lyase inhibitors / T. Kaku, N. Matsunaga, A. Ojida [et al.] // Bioorganic and Medicinal Chemistry. – 2011. – Vol. 19, N 5. – P. 1751–1770. https://doi.org/10.1016/j.bmc.2011.01.017Kaku T., Matsunaga N., Ojida A., Tanaka T., Hara T., Yamaoka M., Kusaka M., Tasaka A. 17,20-Lyase inhibitors. Part 4: design, synthesis and structure-activity relationships of naphthylmethylimidazole derivatives as novel 17,20-lyase inhibitors. Bioorganic and Medicinal Chemistry, 2011, vol. 19, no. 5, pp. 1751–1770. https://doi.org/10.1016/j.bmc.2011.01.017Pharmacophore model-based virtual screening workflow for discovery of inhibitors targeting Plasmodium falciparum Hsp90 / O. Mafethe, T. Ntseane, T. H. Dongola [et al.] // ACS Omega. – 2023. – Vol. 8, N 41. – P. 38220–38232. https://doi.org/10.1021/acsomega.3c04494Mafethe O., Ntseane T., Dongola T. H., Shonhai A., Gumede N. J., Mokoena F. Pharmacophore model-based virtual screening workflow for discovery of inhibitors targeting Plasmodium falciparum Hsp90. ACS Omega, 2023, vol. 8, no. 41, pp. 38220–38232. https://doi.org/10.1021/acsomega.3c04494Pharmacophore modeling and 3D QSAR analysis of isothiazolidinedione derivatives as PTP1B inhibitors / G. S. Deora, P. Joshi, V. Rathore [et al.] // Medicinal Chemistry Research. – 2012. – Vol. 22. – P. 3478–3484. https://doi.org/10.1007/s00044-012-0349-7Deora G. S., Joshi P., Rathore V., Kumar K. L., Ohlyan R., Kandale A. Pharmacophore modeling and 3D QSAR analysis of isothiazolidinedione derivatives as PTP1B inhibitors. Medicinal Chemistry Research, 2012, vol. 22, pp. 3478– 3484. https://doi.org/10.1007/s00044-012-0349-73D-QSAR pharmacophore modeling and in silico screening of phospholipase A2α inhibitors / S. V. Jain, M. Ghate, K. Bhadoriya [et al.] // Medicinal Chemistry Research. – 2012. – Vol. 22. – P. 3096–3108. https://doi.org/10.1007/s00044-012-0316-3Jain S. V., Ghate M., Bhadoriya K. S., Bari S. B., Sugandhi G., Mandwal P. 3D-QSAR pharmacophore modeling and in silico screening of phospholipase A2α inhibitors. Medicinal Chemistry Research, 2012, vol. 22, pp. 3096–3108. https://doi.org/10.1007/s00044-012-0316-3ADMETlab 3.0. – URL: https://admetlab3.scbdd.com (date of access: 17.06.2024).ADMETlab 3.0. Available at: https://admetlab3.scbdd.com (accessed 17 June 2024).Slow-, tight-binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen / E. Cheong, P. C. Nair, R. W. Y. Neo [et al.] // Journal of Pharmacology and Experimental Therapeutics. – 2020. – Vol. 374, N 3. – P. 438–451. https://doi.org/10.1124/jpet.120.265868Cheong E. J. Y., Nair P. C., Neo R. W. Y., Tu H. T., Lin F., Chiong E., Esuvaranathan K., Fan H., Szmulewitz R. Z., Peer C. J., Figg W. D., Chai C. L. L., Miners J. O., Chan E. C. Y. Slow-, tight-binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen. Journal of Pharmacology and Experimental Therapeutics, 2020, vol. 374, no. 3, pp. 438–451. https://doi.org/10.1124/jpet.120.265868

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