Peggy and Harold Katz Family Drug Discovery Center, Division of Nephrology and Hypertension, Department of Medicine and University of Miami, Miami, FL 33176, USA.
Bioorg Med Chem Lett. 2009 Dec 15;19(24):6902-6. doi: 10.1016/j.bmcl.2009.10.077. Epub 2009 Oct 22.
We report the identification of novel small molecule agonists of integrin CD11b/CD18, which increased, in a dose-dependent manner, the adhesion of the integrin CD11b/CD18 expressing cells to two physiologically relevant ligands: Fibrinogen and iC3b. Compound 6 showed an ex vivo EC(50) of 10.5 microM and in vitro selectivity for binding to the recombinant alphaA-domain of CD11b/CD18. In silico docking experiments suggest that the compounds recognized a hydrophobic cleft in the ligand-binding alphaA-domain, implying an allosteric mechanism of modulation of integrin affinity by this novel compound.
我们报告了新型整合素 CD11b/CD18 小分子激动剂的鉴定，这些激动剂以剂量依赖的方式增加了表达整合素 CD11b/CD18 的细胞与两种生理相关配体（纤维蛋白原和 iC3b）的黏附。化合物 6 在体外显示出 10.5 μM 的 EC50，并对与重组 CD11b/CD18 的 alphaA 结构域的结合具有选择性。计算对接实验表明，这些化合物识别配体结合的 alphaA 结构域中的一个疏水性裂缝，这意味着这种新型化合物通过变构机制调节整合素亲和力。
