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Molecular design of multitarget tankyrase and phosphoinositide 3-kinase (PI3K) inhibitorsтезисы доклада
- Авторы: Radchenko E.V., Berishvili V.P., Voronkov A.E., Palyulin V.A., Zefirov N.S.
- Сборник: 21st European Symposium on Quantitative Structure-Activity Relationship: Where Molecular Simulations Meet Drug Discovery, Verona, Italy, September 4-8, 2016
- Тезисы
- Год издания: 2016
- Место издания: Verona, Italy
- Первая страница: P221
- Аннотация: Tankyrase 1 and 2 enzymes have been shown to be promising biological targets for cancer treatment due to their role in the canonical Wnt pathway. Phosphoinositide 3-kinases (PI3K) are also appealing targets for antitumor treatment. Synergetic effects of simultaneous inhibition of these targets were reported. Taking this into account, the goal of the present work was the development of approaches to the design of dual target inhibitors acting concurrently on tankyrase and PI3K. We have developed a virtual screening procedure to identify potential dual target inhibitors. In general, it involves four steps: pharmacophore screening, docking studies, ADMET predictions, and validation of the resulting compound library by the molecular dynamics simulations. The crystal structures of the tankyrase and PI3K enzymes available in the Protein Data Bank (PDB) were used. Pharmacophore models were built using the LigandScout and OpenEye ROCS software. Molecular docking was performed with AutoDock Vina and OpenEye FRED software. For the validation and selection of the pharmacophore and docking models, a database of potent tankyrase and PI3K inhibitors reported in the literature was used, as well as the decoy sets prepared using the standard DUD methodology. The models that provided the highest accuracy and enrichment factors were selected for virtual screening. For the resulting library compounds, some relevant pharmacokinetic properties were predicted using our in-house neural network models and the OCHEM web service. High stability of the Tankyrase and PI3K molecular complexes with the proposed dual target inhibitors was confirmed by the molecular dynamics simulations using the AMBER 14 software. The cross-link between the chemical spaces of compounds with inhibitory activity towards tankyrase and phosphoinositide-3-kinases found in this work opens the way to the development of dual target inhibitors as safe and effective new generation antitumor drugs.
- Добавил в систему: Радченко Евгений Валерьевич