Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein

0541558 - ÚOCHB 2022 RIV DE eng J - Journal Article
Smola, Miroslav - Gutten, Ondrej - Dejmek, Milan - Kožíšek, Milan - Evangelidis, Thomas - Tehrani, Zahra Aliakbar - Novotná, Barbora - Nencka, Radim - Birkuš, Gabriel - Rulíšek, Lubomír - Bouřa, Evžen
Ligand Strain and Its Conformational Complexity Is a Major Factor in the Binding of Cyclic Dinucleotides to STING Protein.
Angewandte Chemie - International Edition. Roč. 60, č. 18 (2021), s. 10172-10178. ISSN 1433-7851. E-ISSN 1521-3773
R&D Projects: GA ČR(CZ) GA20-08772S; GA MŠMT(CZ) EF16_019/0000729
Research Infrastructure: e-INFRA CZ - 90140
Institutional support: RVO:61388963
Keywords : conformational analysis * cyclic dinucleotides * entropy * quantum chemistry * strain energy
OECD category: Physical chemistry
Impact factor: 16.823, year: 2021
Method of publishing: Open access
https://doi.org/10.1002/anie.202016805

STING (stimulator of interferon genes) is a key regulator of innate immunity that has recently been recognized as a promising drug target. STING is activated by cyclic dinucleotides (CDNs) which eventually leads to expression of type I interferons and other cytokines. Factors underlying the affinity of various CDN analogues are poorly understood. Herein, we correlate structural biology, isothermal calorimetry (ITC) and computational modeling to elucidate factors contributing to binding of six CDNs—three pairs of natural (ribo) and fluorinated (2′‐fluororibo) 3′,3′‐CDNs. X‐ray structural analyses of six {STING:CDN} complexes did not offer any explanation for the different affinities of the studied ligands. ITC showed entropy/enthalpy compensation up to 25 kcal mol−1 for this set of similar ligands. The higher affinities of fluorinated analogues are explained with help of computational methods by smaller loss of entropy upon binding and by smaller strain (free) energy.
Permanent Link: http://hdl.handle.net/11104/0319101