Decrypting Integrins by Mixed-Solvent Molecular Dynamics Simulations

Integrins are a familyof & alpha;/& beta; heterodimericcell surfaceadhesion receptors which are capable of transmitting signals bidirectionallyacross membranes. They are known for their therapeutic potential ina wide range of diseases. However, the development of integrin-targetingmedications has been impacted by unexpected downstream effects includingunwanted agonist-like effects. Allosteric modulation of integrinsis 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 withinthe integrin & alpha; I domains of LFA-1 (& alpha;(L)& beta;(2); CD11a/CD18), VLA-1 (& alpha;(1)& beta;(1); CD49a/CD29), and Mac-1 (& alpha;(M)& beta;(2),CD11b/CD18). We show that these pockets are putatively accessibleto small-molecule modulators. The findings reported here may provideopportunities for the design of novel allosteric integrin inhibitorslacking the unwanted agonism observed with earlier as well as currentintegrin-targeting drugs.