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Анализ структуры комплексов белок - лиганд на примере ингибиторов мутантных форм EGFR-киназы

Работа №112506

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химия

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Год сдачи2017
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ПРИНЯТЫЕ СОКРАЩЕНИЯ 9
ВВЕДЕНИЕ 11
1. ЛИТЕРАТУРНЫЙ ОБЗОР 12
1.1. Дизайн ингибиторов киназы 12
1.2. Механизм действия 14
1.3. Рациональный дизайн ингибиторов 19
1.4. Обратимые ингибиторы на основе субстрата 21
1.5. Обратимые ингибиторы на основе АТФ 24
1.6. Ингибиторы бисубстрата 27
1.7. Необратимые ингибиторы на основе субстрата 28
1.8. Необратимые ингибиторы на основе АТФ 30
1.9. Биофлавоноиды и сопутствующие соединения 33
1.10. Агенты химической модификации 36
1.11. Различные ингибиторы 39
2. ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ 43
2.1. Комплекс EGFR(G719S) - лиганд 48
2.2. Комплекс EGFR(L858R) - лиганд 50
2.3. Комплекс EGFR(T790M) - лиганд 52
2.4. Комплекс EGFR(V924R) - лиганд 55
2.5. Комплекс EGFR(T790M, L858R) - лиганд 56
2.6. Прочие комплексы EGFR - лиганд 58
3. ЭКСПЕРИМЕНТАЛЬНАЯ ЧАСТЬ 70
ЗАКЛЮЧЕНИЕ 71
ЛИТЕРАТУРА 72


Современная разработка новых ингибиторов протеинкиназ, при наличии структурных данных о строение фармакологической биомишени включает в себя три основные стадии: молекулярное моделирование, синтез и исследование биологической активности. Несмотря на то, что в последние годы методы молекулярного моделирования значительно усовершенствовались, до сих пор получение данных о строение комплексов белок - лиганд является затратным и рутинным процессом. Одним из основных способом позволяющим более корректно интерпретировать и использовать данные молекулярного моделирования (молекулярного докинга) является использование интегрального подхода, где для конструирования новых ингибиторов используются данные рентгеноструктурного анализа комплексов белок-лиганд совместно с данными молекулярного докинга.
Представленная работа посвящена изучению особенностей межмолекулярного взаимодействия в комплексах мутантных форм киназ семейства рецепторов эпидермального фактора роста с различными низкомолекулярными органическими соединениями (лигандами). Для реализации поставленной цели были решены следующие задачи:
1. Анализ литературных данных об имеющихся рентгеноструктурных данных для комплексов мутантных форм киназ семейства рецепторов эпидермального фактора роста.
2. Обработка и анализ данных рентгеноструктурного анализа для комплексов белок-лиганд. Выявление и систематизация основных межмолекулярных взаимодействий в структуре комплексов белок-лиганд.


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По результатам исследования можно сделать следующие выводы:
1. Проведен детальный анализ экспериментальных данных рентгеноструктурного анализа комплексов белок - лиганд, где в качестве белка выступали различные мутантные формы киназы семейства рецепторов эпидермального фактора роста (содержащие следующие единичные или множественные мутации: G719S, L858R, T790M, V924R, E865A, E866A, K867A, T693S, P694T, V948R).
2. Для исследованных комплексов установлены основные особенности межмолекулярного взаимодействия лиганда c белком, определены ключевые аминокислотные остатки участвующие в связывание лиганда в активном сайте киназного домена рецептора эпидермального фактора роста.
3. Полученные данные имеют большое значение для дальнейшего конструирования высокоаффинных ингибиторов мутантных форм киназ семейства рецепторов эпидермального фактора роста.



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