Discovery of small molecule inhibitors of integrin αvβ3 through structure-based virtual screening

Inhibitors of integrin αvβ3 have been implicated in the treatment of a variety of diseases, including tumor metastasis, neovascularization, osteoporosis, and rheumatoid arthritis. It is therefore desirable to develop new types of small molecule inhibitors of integrin αvβ3. Here we describe the discovery of novel classes of small molecule inhibitors, via structure-based virtual screening, that target the ligand binding site of integrin αvβ3. Application of the docking procedure for screening of a commercially available compound database resulted in a 1774-fold reduction in the size of the screening set (88695 to 50 compounds) and gave a hit-rate of 14% upon biological evaluation (IC50 value ranging from 30 to 200 μM). The best hit, compound 37, 3,4-dichloro-phenylbiguanide, showed inhibitory activity, in a time- and dose-dependent manner, in both cell motility and angiogenesis assays. Based on the best hit, compound 37, a more effective derivative compound 62 has been identified. Furthermore, molecular graphics analyses of a series of substituted phenylbiguanides were carried out to predict the binding mode between the active compounds and integrin αvβ3. Our results indicate that the substituted phenylbiguanides might be involved in the inhibition of bivalent cation-mediated ligand binding of integrin αvβ3.