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.