pharmjournalРазработка и регистрация лекарственных средствDrug development & registration2305-20662658-5049LLC «CPHA»10.33380/2305-2066-2026-15-2-2225pharmjournal-2367Research ArticleПОИСК И РАЗРАБОТКА НОВЫХ ЛЕКАРСТВЕННЫХ СРЕДСТВRESEARCH AND DEVELOPMENT OF NEW DRUG PRODUCTSИнтегрированное компьютерное исследование производных пиримидин-2,4-диона в качестве двойных ингибиторов РНКазы H обратной транскриптазы ВИЧ-1Integrated Computational Exploration of Pyrimidine-2,4-dione Derivatives as Dual HIV-1 RT/RNase H Inhibitorhttps://orcid.org/0000-0003-0134-3294Эль МасаудиЯ.El MasaoudyY.

Лаборатория молекулярной химии и природных веществ, кафедра химии, факультет естественных наук

Мекнес

Molecular chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science

Meknes

https://orcid.org/0000-0002-5281-3156РахманХ. М.RehmanH. M.

Школа биохимии и биотехнологий

Лахор

School of Biochemistry and Biotechnology

Lahore

https://orcid.org/0000-0002-0879-5077АлакарбехМ.AlaqarbehM.https://orcid.org/0000-0002-7731-330XМагатХ.MaghatH.

Лаборатория молекулярной химии и природных веществ, кафедра химии, факультет естественных наук

Мекнес

Molecular chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science

Meknes

https://orcid.org/0000-0003-4917-475XЛахлифиТ.LakhlifiT.

Лаборатория молекулярной химии и природных веществ, кафедра химии, факультет естественных наук

Мекнес

Molecular chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science

Meknes

https://orcid.org/0000-0002-8901-047XБуахринМ.BouachrineM.

Лаборатория молекулярной химии и природных веществ, кафедра химии, факультет естественных наук

Мекнес

Molecular chemistry and Natural Substances Laboratory (MCNSL), Department of Chemistry, Faculty of Science

Meknes

m.bouachrine@umi.ac.maУниверситет Мулая ИсмаилаМароккоUniversity of Moulay IsmailMoroccoУниверситет ПенджабаПакистанUniversity of the PunjabPakistanНаучно-исследовательский центр прикладных наук, Частный университет прикладных наукИорданияApplied Science Research Center, Applied Science Private UniversityJordan2026110620261524357Copyright © Эль Масауди Я., Рахман Х.М., Алакарбех М., Магат Х., Лахлифи Т., Буахрин М., 20262026Эль Масауди Я., Рахман Х.М., Алакарбех М., Магат Х., Лахлифи Т., Буахрин М.El Masaoudy Y., Rehman H.M., Alaqarbeh M., Maghat H., Lakhlifi T., Bouachrine M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmjournal.ru/jour/article/view/2367Введение

Введение. Постоянные усилия по поиску новых противовирусных средств, нацеленных на РНКазу H обратной транскриптазы ВИЧ обусловлены высокой заболеваемостью и неуклонным ростом смертности. Настоящее исследование сосредоточено на десяти основанных на пиримидин-2,4-дионе молекулах, которые, как было установлено, обладают мощной противовирусной активностью против РНКазы H обратной транскриптазы ВИЧ, а также достаточной биодоступностью и фармакокинетическими свойствами.

Цель

Цель. Поиск и оценка перспективных производных молекул пиримидин-2,4-диона в качестве потенциальных ингибиторов ВИЧ.

Материалы и методы

Материалы и методы. Для изучения механизмов связывания спроектированных соединений с активным центром РНКазы H был использован протокол докинга с применением программы AutoDock Vina. Молекулярно динамическое моделирование продолжительностью 100 нс выполнялось в программе Desmond, комплексы были построены на основе силового поля OPLS3 2005. Энергии фронтальных молекулярных орбиталей и связанные с ними показатели реакционной способности наиболее эффективных антивирусных агентов были рассчитаны с помощью метода DFT B3LYP/6 31G(d,p), реализованного в программе Gaussian

Результаты и обсуждение

Результаты и обсуждение. Две молекулы, Pyr06 и Pyr07, продемонстрировали более высокий показатель докинга (−10,7 ккал/моль) в сравнении с контрольным соединением (MPD: −9,8 ккал/моль) и с другими спроектированными соединениями (с аффинностями в диапазоне от −9,6 до −10,4 ккал/моль). С другой стороны, было отмечено, что эти две молекулы образуют значительное количество водородных связей и гидрофобных контактов с аминокислотными остатками активного центра. Кроме того, анализ, проведенный с помощью молекулярно динамического моделирования в течение 100 нс, подтвердил устойчивость связывания и конформацию молекул Pyr06 и Pyr07 в комплексах с рецептором 5J1E. Квантово химические расчеты DFT для обоих соединений, Pyr06 и Pyr07, также подтвердили их высокие показатели докинга и способность образовывать стабильные комплексы с РНКазой H.

Заключение

Заключение. Полученные результаты могут оказаться крайне полезными для разработки соединений Pyr06 и Pyr07 в качестве потенциальных терапевтических препаратов для борьбы с РНКазой H обратной транскриптазы ВИЧ.

Introduction

Introduction. Continuous efforts to uncover new antiviral entities targeting HIV RT RNase H stem from the suffering of affected individuals and the relentless increase in death cases. The present study focused on ten molecules based on the pyrimidine-2,4-dione scaffold, which were discovered to have potent antiviral activity against HIV RT RNase H and acceptable bioavailability and pharmacokinetic properties.

Aim

Aim. The main goal of this study is to discover and evaluate promising pyrimidine-2,4-dione-derived molecules as potential inhibitors of HIV.

Materials and methods

Materials and methods. A docking protocol was executed to investigate the binding mechanisms of the designed compounds within RNase H's active site using the AutoDock Vina program. The molecular dynamics simulation analysis for 100 ns was carried out using Desmond, and the complexes were constructed using the OPLS3-2005 force field. The frontier molecular orbital energies and related reactivity factors of the best antiviral agents were determined using the DFT-B3LYP/6-31G (d,p) calculations performed with the Gaussian program.

Results and discussion

Results and discussion. Two molecules, Pyr06 and Pyr07, displayed a higher docking score (–10.7 kcal/mol) than the control compound (MPD: –9.8 kcal/mol) and the other designed compounds (with affinities ranging from –9.6 to –10.4 kcal/mol). On the other hand, it was noted that these two molecules formed significant hydrogen bonds and hydrophobic contacts with active site residues. Furthermore, our analysis through MD simulations for 100 ns validated the binding stability and conformation of molecules Pyr06 and Pyr07 in complexes with the 5J1E receptor. The DFT findings for both molecules, Pyr06 and Pyr07, also confirmed their docking scores and their ability to form stable complexes with RNase H.

Conclusion

Conclusion. The results obtained could be highly beneficial for designing and developing Pyr06 and Pyr07 as potential therapeutic drugs to combat HIV RT RNase H.

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