Speaker
Description
Computational treatment of ligand:protein interactions represents an old, but yet unsolved challenge in theoretical chemistry. The hybrid quantum mechanical and molecular mechanical (QM/MM) approach, combined with X-ray crystallography, molecular docking and conformational sampling, seems to be the most promising approach for the computational ligand (drug) design. The accuracy of the QM/MM approaches, though, comes at a price of huge computational resources requested by the calculations which are available in supercomputer centres.
Specifically, within the OPEN-15-18 IT4I project, we focused on the stimulator of interferon genes (STING), a protein that is central to the immune system and whose activation and inhibition represents an underexplored therapeutic target in medicinal chemistry. The natural ligand of the STING is the cyclic dinucleotide 2′,3′-cGAMP (cyclic [G(2′,5′)pA(3′,5′)p]), which is synthetized by the cyclic- GMP-AMP synthase, upon detection of the double-stranded DNA in the cytosol which then initiates the immune response.
Our computational efforts, carried out at the IT4I supercomputer center, aimed at (1) the quantitative evaluation and interpretation of the observed STING:CDN binding constants (CDN= cyclic dinucleotide), (2) elucidation of the structural and energetic details accompanying the STING ligand binding and ultimately to (3) predictions of new molecular scaffolds to synthesized and tested experimentally. [1-7]
[1] Gutten, O. et al. Phys. Chem. Chem. Phys. 2021, 23, 7280-7294.
https://doi.org/10.1039/D0CP05993E
[2] Novotná, B. et al.: Enzymatic Preparation of 2‘-5‘, 3‘-5‘Cyclic Dinucleotides, Their Binding Properties to Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations. J. Med. Chem. 2019, 62, 10676-10690.
https://doi.org/10.1021/acs.jmedchem.9b01062
[3] Pimková Polidarová, M.; Břehová, P.; Kaiser, M. M.; Smola, M.; Dračínský, M.; Smith, J.; Marek, A.; Dejmek, M.; Šála, M.; Gutten, O.; Rulíšek, L.; Novotná, B.; Brázdová, A.; Janeba, Z.; Nencka, R.; Boura, E.; Páv, O.; Birkuš, G.*: Synthesis and Biological Evaluation of Phosphoester and Phosphorothioate Prodrugs of STING Agonist 3′,3′-c-Di(2′F,2′dAMP). J. Med. Chem. 2021, 64,7596–7616
https://doi.org/10.1021/acs.jmedchem.1c00301
[4] Smola, M.; Gutten, O.; Dejmek, M.; Kožíšek, M.; Evangelidis, T.; Aliakbar Tehrani, Z.; Novotná, B.; Nencka, R.; Birkuš, G.; Rulíšek, L.; Boura, E.: Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein. Angew. Chem. Int. Ed. 2021, 60, 10172–10178.
https://doi.org/10.1002/anie.202016805
[5] Vavřina, Z.; Gutten, O.; Smola, M.; Zavřel, M.; Aliakbar Tehrani, Z.; Charvát, V.; Kožíšek, M.; Boura, E.; Birkuš, G.; Rulíšek, L.*: Protein-Ligand Interactions in the STING Binding Site Probed by Rationally Designed Single-Point Mutations: Experiment and Theory Biochemistry 2021, 60, 607 620.
https://doi.org/10.1021/acs.biochem.0c00949
[6] Aliakbar Tehrani, Z.;* Rulíšek, L.; Černý, J.: Molecular dynamics simulations provide structural insight into binding of cyclic dinucleotides to human STING protein. J. Biomol. Struct. Dyn. 2021
https://doi.org/10.1080/07391102.2021.1942213.
[7] Novotná, B.; Holá, L.; Staś, M.; Gutten, O.; Smola, M.; Zavřel, M.; Vavřina, Z.; Buděšínský, M.; Liboska, R.; Chevrier, F.; Dobiaš, J.; Boura, E.; Rulíšek, L.; Birkuš, G.*: Enzymatic Synthesis of 3′–5′, 3′–5′ Cyclic Dinucleotides, Their Binding Properties to the Stimulator of Interferon Genes Adaptor Protein, and Structure/Activity Correlations. Biochemistry 2021, 60, 3714–3727.
https://doi.org/10.1021/acs.biochem.1c00692
