Binding mode of a highly potent and orally active $\alpha 4 \beta 1$ antagonist determined by Free Energy Perturbation calculations

ERNESTO R. CAFFARENA; CARLOS M. CARLEVARO; WILSON SAVINO

Ouro Preto

Simposio; Brazilian Symposium on Medicinal Chemistry; 2010

The a4b1 integrin or very late antigen-4 (VLA-4) belongs to the heterodimeric integrin receptor superfamily. VLA-4 is expressed on the surface of most leukocytes and binds to vascular cell adhesion molecule-1 (VCAM-1) and the CS-1 domain of fibronectin. VCAM-1 is expressed on activated endothelial cells in response to inflammatory cytokines. Adhesion interactions between VLA-4 and VCAM-1 may be important for activation, migration, proliferation, and differentiation of leukocytes during normal and pathophysiological processes. This has generated significant interest in the development of small molecule antagonists of VLA-4 for the treatment of diseases where cell-trafficking and activation are important, asthma, rheumatoid arthritis and multiple sclerosis. In this context, the theoretical and computational study of the molecular bases involved in the recognition process is today a crucial stage of the rationale to obtain therapeutically useful drugs. The knowledge of the right binding mode between ligands and their receptors allows the identification of crucial amino acids involved in the recognition process.