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Оценка in silico ингибирующей активности производных 1,2,4-триазоло[4,3-?]пиразина в отношении резистентного малярийного паразита (Plasmodium falciparum) с помощью методов DFT, молекулярного докинга и ADMET
Аннотация
Малярия, которая передается людям главным образом через укусы инфицированных плазмодием самок комаров Anopheles, в настоящее время остается серьезной проблемой глобального здравоохранения. Появление устойчивости к противомалярийным препаратам, обусловленной отбором паразитов с генетическими мутациями или усилением генов, усложняет стратегии лечения, часто требуя более высоких доз или комбинаций лекарств. Несмотря на эти усилия, успехи в борьбе с малярией остаются ограниченными, поэтому необходимы постоянные исследования в области проектирования и разработки новых лекарств для решения этих проблем. Для оценки противомалярийной активности 14 гибридных соединений 1,2,4-триазоло[4,3-a]пиразина использовали методы in silico. Ингибирующую эффективность соединений против Plasmodium falciparum оценивали с использованием теории функционала плотности, молекулярного докинга и профилирования ADMET (абсорбция, распределение, метаболизм, экскреция и токсичность). Результаты сопоставления соединений с миозином А P. falciparum показали, что соединения L2, L9, L10 и L14 являются лигандами с наибольшим сродством связывания. Граничные орбитали и электростатический потенциал указывают на роль 1,2,4-триазоло[4,3-a]пиразинового фрагмента в качестве основного центра, контролирующего терапевтическую активность, и на то, что атомы азота в 1,2,4-триазоло[4,3-a]пиразиновом фрагменте являются нуклеофильными центрами, которые могут способствовать взаимодействию лиганд – рецептор. Анализ ADMET показал, что соединения L2, L9, L10 и SD2 (пуромицин) могут проникать через гематоэнцефалический барьер, что предполагает потенциальное распространение в центральной нервной системе. Однако критический анализ физико-химических и фармакокинетических данных показал, что соединение L6 может быть лучшим лекарственным средством.
DOI: 10.30906/2073-8099-2024-16-6-16-33Ключевые слова
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