Civera Monica, Arosio Daniela, Bonato Francesca, Manzoni Leonardo, Pignataro Luca, Zanella Simone, Gennari Cesare, Piarulli Umberto, Belvisi Laura
Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, I-20133 Milano, Italy.
Istituto di Scienze e Tecnologie Molecolari (I.S.T.M.), Consiglio Nazionale delle Ricerche (C.N.R.), via Golgi 19, I-20133 Milano, Italy.
Cancers (Basel). 2017 Sep 21;9(10):128. doi: 10.3390/cancers9100128.
The interaction of a small library of cyclic RGD (Arg-Gly-Asp) peptidomimetics with αβ₆ integrin has been investigated by means of competitive solid phase binding assays to the isolated receptor and docking calculations in the crystal structure of the αβ₆ binding site. To this aim, a rigid receptor-flexible ligand docking protocol has been set up and then applied to predict the binding mode of the cyclic RGD peptidomimetics to αβ₆ integrin. Although the RGD interaction with αβ₆ recapitulates the RGD binding mode observed in αβ₃, differences between the integrin binding pockets can strongly affect the ligand binding ability. In general, the peptidomimetics exhibited IC values for integrin αβ₆ (i.e., the concentration of compound required for 50% inhibition of biotinylated fibronectin binding to isolated αβ₆ integrin) in the nanomolar range (77-345 nM), about 10-100 times higher than those for the related αβ₃ receptor, with a single notable ligand displaying a low nanomolar IC value (2.3 nM). Insights from the properties of the binding pocket combined with the analysis of the docking poses provided a rationale for ligand recognition and selectivity.
通过对分离出的受体进行竞争性固相结合测定以及对αβ₆结合位点晶体结构进行对接计算，研究了一个小型环状RGD（精氨酸-甘氨酸-天冬氨酸）拟肽文库与αβ₆整合素的相互作用。为此，建立了一种刚性受体-柔性配体对接方案，然后将其应用于预测环状RGD拟肽与αβ₆整合素的结合模式。尽管RGD与αβ₆的相互作用重现了在αβ₃中观察到的RGD结合模式，但整合素结合口袋之间的差异会强烈影响配体的结合能力。一般来说，这些拟肽对整合素αβ₆的IC值（即抑制生物素化纤连蛋白与分离出的αβ₆整合素结合50%所需的化合物浓度）在纳摩尔范围内（77 - 345 nM），比相关的αβ₃受体高出约10 - 100倍，只有一种显著的配体显示出低纳摩尔IC值（2.3 nM）。结合口袋特性的见解与对接构象分析相结合，为配体识别和选择性提供了理论依据。
