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Decrypting Integrins by mixed-solvent molecular dynamics simulations

I.M. Ilie; C. Ehrhardt; A. Caflisch; G. Weitz-Schmidt

Journal: J. Chem. Inf. Model.
Year: 2023
Volume: 63
Pages: 3878–3891
DOI: 10.1021/acs.jcim.3c00480
Type of Publication: Journal Article

allostery; 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.