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Decrypting Integrins by Mixed-Solvent Molecular Dynamics Simulations.

ABSTRACT: 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 (α_Lβ₂; CD11a/CD18), VLA-1 (α₁β₁; CD49a/CD29), and Mac-1 (α_Mβ₂, 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.

SUBMITTER: Ilie IM

PROVIDER: S-EPMC10302478 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Decrypting Integrins by Mixed-Solvent Molecular Dynamics Simulations.

Ilie Ioana M IM Ehrhardt Claus C Caflisch Amedeo A Weitz-Schmidt Gabriele G

Journal of chemical information and modeling 20230613 12

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-solv ...[more]

PMID: 37310029

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Dataset Information

Decrypting Integrins by Mixed-Solvent Molecular Dynamics Simulations.

Publications

Decrypting Integrins by Mixed-Solvent Molecular Dynamics Simulations.

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