Молекулярное моделирование строения и функционирования метаботропных глутаматных рецепторов и компьютерный дизайн их потенциальных лигандов тема диссертации и автореферата по ВАК РФ 02.00.03, кандидат химических наук Беленикин, Максим Сергеевич

• Беленикин, Максим Сергеевич
• кандидат химических наук
• 2004

Оглавление диссертации кандидат химических наук Беленикин, Максим Сергеевич

Введение.

Глава 1. Литературный обзор.

1.1. Сигнальная система.

1.2. G-Белок сопряженные рецепторы.

1.3. Классификация глутаматных рецепторов.

1.4. Семейство метаботропных глутаматных рецепторов.

1.5. Пространственное строение mGlu рецепторов.

1.6. Лиганды mGlu рецепторов.

1.6.1. Агонисты I группы mGlu рецепторов.

1.6.2. Агонисты II группы mGlu рецепторов.

1.6.3. Агонисты III группы mGlu рецепторов.

1.6.4. Антагонисты mGlu рецепторов.

1.6.5. Неконкурентные антагонисты и аллостерические модуляторы.

1.7. Модели активации и функционирования mGlu рецепторов.

1.8. Распознавание и связывание лигандов mGlu рецепторами.

1.9. Агонист-независимая активность mGlu рецепторов.

1.10. Модуляция mGlu рецепторов катионами кальция.

1.11. Димеризация и гликозилирование mGlu рецепторов и их роль в активации mGlu рецепторов.

1.12. Передача сигналов mGlu рецепторами.

1.12.1. Области, участвующие в сопряжении с G-белками и их активации.

1.12.2. Влияние сплайсинг-варианта СКД на передачу сигнала.

1.12.3. Передача сигнала mGlu рецепторами не через G-белки.

1.12.4. Взаимодействие mGlu рецепторов с Homer- и RGS-белками.

1.12.5. Фосфорилирование и его влияние на функционирование mGlu рецепторов, участие РКС в процессе десенситизации mGlu рецепторов.

Введение диссертации (часть автореферата) на тему «Молекулярное моделирование строения и функционирования метаботропных глутаматных рецепторов и компьютерный дизайн их потенциальных лигандов»

5.2. Молекулярный докинг лигандов.110

5.2.1. Докинг лигандов с применением автоматического подхода.110

5.2.2. Молекулярный докинг лигандов с применением ручного подхода.! 17

5.3. Оценочные функции.119

5.4. Подходы к направленному de novo конструированию лигандов.120

5.5. Применимость молекулярного докинга лигандов.121

Глава 6. Автоматический докинг баз данных органических структур.121

6.1. Введение.121

6.2. Подготовка данных и проведение расчетов.122

6.3. Распознавание активных лигандов и обогащение баз данных.128

6.4. Использование структурных генераторов для создания баз данных.132

6.5. Расположение лигандов в междольной полости mGlu рецепторов.132

6.6. Эффективность виртуального скрининга в случае mGlu рецепторов.133

Глава 7. Молекулярный докинг потенциальных лигандов mGlu рецепторов. 134

7.1. Направленная модификация известных лигандов.134

7.2. Направленная модификация селективного антагониста AID А.138

7.3. Производные триангуланов.142

7.4. Производные бицикло[3.3.1]нонанов и бицикло[2.2.1]гептанов.145

7.5. Структурные модификации для увеличения селективности лигандов.146

7.6. Выводы о возможных вариациях структур лигандов.147

Глава 8. Молекулярно-динамические расчеты.148

8.1. Теоретическое введение.148

8.2. Оценка свободных энергий связывания для лиганд-рецепторных комплексов

150

8.3. Расчеты положения антагонистов в ЛСЦ mGlu рецепторов.152

8.4. МД расчеты процессов схлопывания АКД mGlul рецептора.157

8.5. Сравнение схем расчета дальнего электростатического взаимодействия при

МД моделировании процессов схлопывания АКД mGlul рецептора.164

8.6. Влияние лиганда на динамическое поведение АКД на начальных стадиях его открытия и закрытия.167

8.7. МД моделирование поведения димера АКД mGlul рецептора.169

8.8. Направленная молекулярная динамика.173

8.9. МД расчеты лиганд-рецепторных комплексов (при ограниченном размере моделируемых областей) для сравнительного анализа поведения лигандов в ЛСЦ разных подтипов mGlu рецепторов.176

8.10. МД расчеты фрагмента липидного бислоя и димера ТМД в нем.179

Глава 9. Модель функционирования mGlu рецепторов.181

9.1. Описание модели.181

9.2. Влияние меж- и внутридоменных взаимодействий на эффективность передачи сигнала и функционирование mGlu рецепторов; модель для объяснения различий в эффективности и селективности лигандов.186

Заключение диссертации по теме «Органическая химия», Беленикин, Максим Сергеевич

ВЫВОДЫ

С помощью метода моделирования по гомологии впервые построены пространственные модели внеклеточных аминоконцевых лиганд-связывающих доменов mGlu2-mGlu8 подтипов метаботропных глутаматных рецепторов и проведен сравнительный анализ строения сайтов связывания конкурентных лигандов всех известных в настоящее время восьми подтипов этих рецепторов.

2. Осуществлено построение пространственных моделей трансмембранных доменов mGlu рецепторов, содержащих сайт связывания неконкурентных антагонистов и аллостерических модуляторов на основе структуры родопсина. Построена модель димера трансмембранных доменов mGlul рецептора.

3. Проведено изучение белок-лигандных взаимодействий для серии известных лигандов как для открытых, так и закрытых форм всех восьми подтипов mGlu рецепторов с помощью молекулярного докинга, позволившее рассчитать строение лиганд-рецепторных комплексов и качественно объяснить зависимости структура-активность для лигандов mGlu рецепторов.

4. Выполнено исследование возможных направлений модификации лигандов с целью улучшения их связывания с mGlu рецепторами всех подтипов и отобраны серии перспективных структур для дальнейшего их изучения.

5. Реализована ориентированная на метаботропные глутаматные рецепторы система виртуального скрининга баз данных органических соединений для поиска потенциальных лигандов mGlu рецепторов всех подтипов. В результате проведения виртуального скрининга получены сфокусированные библиотеки соединений, в десятки и сотни раз обогащенные потенциальными лигандами mGlu рецепторов по сравнению с исходной базой.

6. С использованием методологии протягивания проведена оценка вариантов пространственной укладки для доменов, богатых цистеиновыми остатками в группе метаботропных глутаматных рецепторов, а также С-концевых доменов (для mGlu рецепторов I группы), важных для функционирования рецептора.

7. Проведено построение полной структурной модели димера mGlu рецептора на примере mGlul, позволяющая объяснить особенности их функционирования при взаимодействии с лигандами.

8. Проведенные молекулярно-динамические расчеты лиганд-рецепторных комплексов и свободных форм рецепторов позволили предсказать и объяснить: агонист-подобное расположение антагонистов в лиганд-связывающих центрах mGlu рецепторов (было подтверждено экспериментально в литературе), важное функциональное значение димеризации аминоконцевых доменов, возможность моделирования процессов закрытия и открытия аминоконцевого домена, а также предположить альтернативное объяснение функциональной роли агонистов, заключающееся в изменении конформаций боковых цепей аминокислотных остатков.

ЗАКЛЮЧЕНИЕ

Таким образом, в данной работе, исходя из аминокислотной последовательности была построена первая полная структура димера mGlu рецептора (на примере mGlul рецептора) и предложена модель его функционирования. Была развита и опробована методология поиска потенциальных лигандов с помощью системы виртуального скрининга баз данных низкомолекулярных органических соединений, оценены возможные направления модификаций известных лигандов и сконструированы новые потенциальные лиганды mGlu рецепторов.

Основная работа выполнена при финансовой поддержке Российского фонда фундаментальных исследований (проекты: 98-03-32955, 02-03-32790, 03-04-58740, 0303-32630), Миннауки РФ, Минпромнауки РФ (направление "Компьютерное конструирование новых лекарственных средств") и правительства Италии (Accordo di cooperazione scientifica).

Автор признателен профессорам Роберто Пелличари и Габриэле Костантино (университет г. Перуджа, Италия) за ряд ценных критических замечаний и обсуждений, проводимых на разных этапах работы, а также за возможность выполнения части работы в Университете г. Перуджа (Италия).

Автор выражает благодарность НИИБМХ РАМН (проф. А.С.Иванову, проф. В.В.Поройкову, к.б.н. В.С.Скворцову) за научную и техническую помощь на начальных этапах работы и фирмам Tripos GmbH (Мюнхен, ФРГ), Catalyst Silicon Solutions (Россия), VISTGroup (Россия), NCgroup (Россия) за техническую поддержку на разных этапах работы.

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