danДоклады Национальной академии наук БеларусиDoklady of the National Academy of Sciences of Belarus1561-83232524-2431The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1561-8323-2019-63-1-37-43dan-583Research ArticleХИМИЯCHEMISTRYВиртуальный скрининг пиррол-содержащих структурных аналогов иматиниба методом молекулярного докингаDocking-based virtual screening of pyrrole containing imatinib structure analogsФаринаА. В.FarinaA. V.

Фарина Александр Васильевич - научный сотрудник.

Ул. Купревича, 5/2, 220141, Минск

Farina Alexander Vasilievich - Researcher.

5/2, Kuprevich Str., 220141, Minsk

farina@iboch.byИнститут биоорганической химии, Национальная академия наук БеларусиInstitute of Bioorganic Chemistry, National Academy of Sciences of Belarus2019110320196313743Copyright © Фарина А.В., 20192019Фарина А.В.Farina A.V.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/583

Ингибиторы тирозинкиназ стали общепринятым стандартом в лечении хронического миелоидного лейкоза. Однако вторичная резистентность пациентов, часто развивающаяся с течением заболевания, обуславливает необходимость поиска новых эффективных киназных ингибиторов. В данной работе с помощью программного обеспечения Autodock Vina был осуществлен молекулярный докинг комбинаторной библиотеки структур, сконструированных de novo. При этом основной подход к дизайну заключался в замене бензольного линкера в структуре иматиниба на пиррольный фрагмент. В качестве рецепторов использовались структуры киназ C-ABL, Human ABL и T315I-мутантная ABL. Подготовка лигандов проводилась средствами пакета MGL Tools. Подготовка рецепторов, определение размеров и положения активного центра фермента, анализ и визуализация результатов осуществлялись в программе Chimera 1.10. Для параметра интенсивности поиска (exhaustiveness) Autodock Vina было установлено значение 24. На основании сравнения с результатами докинга известных ингибиторов иматиниба и нилотиниба исследуемые структуры были отфильтрованы. Выбраны две наиболее перспективные структуры, для которых оценка энергии связывания Autodock Vina score составила -13,6 и -13,1 соответственно.

Tyrosine kinase inhibitors became a common treatment option for chronic myelogenous leukemia (CML). Still secondary resistance of patients connected with disease progression remains a major challenge. More effective kinase inhibitors are of great need. In this study, design and molecular docking of combinatory library of de novo imatinib-like structures was performed using Autodock Vina. The main design approach was to replace a benzene linker in the structure of imatinib with a pyrrole ring. Crystal structures of CML-related C-ABL, Human ABL and T315I mutant ABL were used as receptors. Ligands were prepared in MGL Tools. Chimera 1.10 was used for receptor preparation, binding site parametrization and visualization of results. Vina’s exhaustiveness of search was set to 24. All docked structures were filtered based on the known inhibitors results. Two structures showed the promising predicted binding affinities (Autodock Vina’s score -13.6 and -13.1 respectively) comparable with those of approved kinase inhibitors imatinib and nilotinib.

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