Trajectories and Comparative Analysis of Compounds that Bind α4β1 and α4β7

Integrins, a family of α/β transmembrane heterodimeric adhesion molecule Receptors, help cells communicate to each other in the extracellular matrix. These receptors are expressed on the majority of white blood cells, including subtypes like leukocytes, lymphocytes, monocytes, basophils and eosinophils. When α4β1 is bound to\VCAM-1 it induces an inflammatory response. Likewise, the binding of α4β7 and MAdCAM-1, causes the specific inflammatory response of T-cell homing to inflamed gut-associated lymphoid tissue. The goal of my research is to find drug candidates that will effectively inhibit α4β7 to treat Crohn’s disease and Ulcerative Colitis. Vedolizumab, which selectively targets integrin α4β7, had positive outcomes in GEMINI trials, but costs $31.6 Billion/yr. Our goal, is to develop a once-a-day pill that is cheaper and eliminates the requirement for indefinite clinical injections. I hypothesize that simulations and analysis of drug candidate protein binding will allow modifications of lead drugs that could make them more selective for α4β7. I am using the Research-Computing-Data-Core at UH to model α4β1 and α4β7 and dock computational libraries. The ligands are energy minimized and topologies generated for simulation. I am working to create safe, cost-effective therapeutic strategies that might someday lead to better treatments for Crohn’s or IBD. This project was completed with contributions from Ronald Biediger, Peter Vanderslice, and Darren Woodside from the Texas Heart Institute and from David Maxwell from the University of Texas MD Anderson Cancer Center.