Binding Model for Nonpeptide Antagonists of αvβ3 Integrin

A binding model for nonpeptide antagonists of integrin αvβ3 has been developed through docking analyses utilizing the MMFFs force field and the recently published crystal structure, 1JV2. Results of this docking study have led to the identification of a novel binding model for selective antagonists of αvβ3 over αIIbβ3 integrins. Four different chemical classes are shown to bind in a similar fashion providing a measure of confidence in the proposed model. All αvβ3 and αIIbβ3 antagonists have a basic nitrogen separated some distance from a carboxylic acid to mimic RGD. For the αvβ3 antagonists under present consideration, these charged ends are separated by twelve bonds. The basic nitrogen of the active αvβ3 ligands are shown to interact with D150 of αv and the ligands' carboxylic acid interact with R214 of β3 while adopting an extended conformation with minimal protein induced internal strain. In addition, an energetically favorable interaction is found with all of the active αvβ3 molecules with Y178 of αv...