Молекулярний дизайн та спрямований синтез нових сполук з противірусною активністю по відношенню до вірусу грипу птахів

Abstract

З використанням QSAR-технології розроблено та застосовано моделі, які дозволяють встановити кількісний зв’язок між структурою сполук та їх протигрипозною активністю. За допомогою цих моделей проведено віртуальний скринінг, молекулярний дизайн, а також спрямований синтез сполук, які мали високий рівень прогнозованої протигрипозної активності, а також проявляли аналогічну дію в експерименті стосовно вірусу грипу птахів H5N3 на культурі тканини. Застосування запропонованого підходу дозволить спростити пошук та синтез речовин, які в подальшому можуть бути використані в якості противірусних препаратів.

The influenza virus causes the greatest number of acute respiratory viral infections, which can lead to an exacerbation of chronic systemic diseases, to emergence of bacterial complications, to a significant deterioration of public health. The goal of the work. The main scope of the investigation was creation of compounds with high activity against avian influenza with the QSAR technology. For the realization of this scope we have to: 1. develop the original software for the QSAR analysis aimed at the molecular design of the compounds with high predicted antiviral activity against avian influenza; 2. conduct directed synthesis of such compounds; 3. determine activity of the new synthesized compounds in vitro against the strain of the avian virus H5N3; 4. compare the experimental anti-influenza activity with the predicted activity calculated with the QSAR technology. Materials and methods. The anti-influenza activity of the compounds was studied in vitro against the avian virus H5N3 using tissue culture of chorio-allantoic membranes of 10-12-days chicken embryos (CAM). Results of research and discussion. 25 out of 37 new synthesized compounds have confirmed the high level of predicted activity in the experiment in the tissue of CAM culture. The level of predicted activity of 3 compounds was higher than that obtained in the experiment. The experimental level of anti-influenza activity of 9 compounds exceeded the level of predicted activity. Thus, using the QSAR technologies, synthesis of substances was carried out, which showed 67.57% of the predicted properties in the experiment. Conclusions and prospects for further research. Models making it possible to establish a quantitative relationship between the structure of compounds and their anti-influenza activity have been developed and applied. The molecular design and directed synthesis of compounds with a high level of predicted activity were carried out with the help of these models. The level of predicted activity was confirmed in the experiment in the tissue of CAM culture against avian influenza H5N3. Application of the proposed approach makes it possible to simplify the search and synthesis of substances that can later be used as antiviral drugs.

С использованием QSAR-технологии разработаны и применены модели, позволяющие установить количественную связь между структурой соединений и их противогриппозной активностью. С помощью этих моделей проведен виртуальный скрининг, молекулярный дизайн и направленный синтез соединений, имеющих высокий уровень прогнозированной активности, который подтверждался в эксперименте в отношении вируса гриппа птиц H5N3 на тканевой культуре. Применение предложенного подхода позволяет упростить поиск и синтез веществ, которые в дальнейшем могут быть использованы в качестве противовирусных препаратов.