28 June 2023
Integrins are a family of 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 medication has been impacted by unexpected downstream effects. In particular, these are observed with drugs targeting the native binding site of the integrin.
The so-called allosteric modulation of integrins is a promising approach to potentially overcome these limitations. Here, the drug binds elsewhere on the receptor, changing the conformation and thus impacting the activity of the protein. Allosteric modulation of receptors therefore creates opportunities for drug discovery and development which are potentially superior to classic orthosteric modulation.
The novel computational approach developed by Ioana Ilie relies on enriching the solvent with small organic molecules (benzene in small concentrations) to enable the gentle opening of the integrin α I domain. This revealed novel previously inaccessible druggable pockets within the integrins LFA-1, VLA-1, and Mac-1. This study thus offers structural and dynamic insight on the effect of small alterations in solvent conditions on the accessibility of novel potentially druggable pockets, which are validated via virtual screening. The study acts as proof of concept and sets the foundation for the design of the next-generation integrin-targeting drugs. Additionally, it opens new research avenues towards the identification of allosteric sites in other up to date undruggable protein targets.
Finally, the study goes beyond drug discovery as it demonstrates that minor changes in the solvent conditions can have a dramatic impact on the conformational space of the solvated molecule. This offers the opportunity to tune the solvent conditions in order to obtain a specific response of the solvated molecule (e.g. protein, material), which implicitly can aid in the development novel bio-inspired materials with responsive properties.
Ioana M. Ilie, C. Ehrhardt, A. Caflisch and G. Weitz-Schmidt: Decrypting integrins by mixed-solvent molecular dynamics simulations. J. Chem. Inf. Model. 2023, 63, 12, 3878–3891. DOI: 10.1021/acs.jcim.3c00480