Decrypting Integrins by mixed-solvent molecular dynamics simulations

TitleDecrypting Integrins by mixed-solvent molecular dynamics simulations
Publication TypeJournal Article
Year of Publication2023
AuthorsIlie I.M., Ehrhardt C., Caflisch A., Weitz-Schmidt G.
JournalJournal of Chemical Information and Modeling
Date Published2023 June 13
Type of ArticleResearch Article
Keywordsallostery, integrins, molecular dynamics simulations, SEED

Integrins are a family of α/β heterodimeric cell surface adhesion receptors which are capable of transmitting signals bidirectionally across membranes. They are known for their therapeutic potential in a wide range of diseases. However, the development of integrin-targeting medications has been impacted by unexpected downstream effects including unwanted agonist-like effects. Allosteric modulation of integrins is a promising approach to potentially overcome these limitations. Applying mixed-solvent molecular dynamics (MD) simulations to integrins, the current study uncovers hitherto unknown allosteric sites within the integrin α I domains of LFA-1 (αLβ2; CD11a/CD18), VLA-1 (α1β1; CD49a/CD29), and Mac-1 (αMβ2, CD11b/CD18). We show that these pockets are putatively accessible to small-molecule modulators. The findings reported here may provide opportunities for the design of novel allosteric integrin inhibitors lacking the unwanted agonism observed with earlier as well as current integrin-targeting drugs.



Alternate JournalJ. Chem. Inf. Model.
PubMed ID37310029
PubMed Central IDPMC10302478