Madeleine Noelly, Gardebien Fabrice
DSIMB, INSERM, U1134, Paris, F-75015, France and Universite de la Reunion, UMR_S 1134, Faculte des Sciences et Technologies, 15, avenue Rene Cassin, BP 7151, 97715 Saint Denis Messag Cedex 09, La Reunion, France and Institut National de la Transfusion Sanguine, F-75015 Paris, France.
Curr Comput Aided Drug Des. 2018;14(3):253-268. doi: 10.2174/1573409912666160719093244.
Drepanocytosis is a genetic blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. In the pathogenesis of vaso-occlusive crises of sickle cell disease, red blood cells bind to the endothelium and promote vaso-occlusion. At the surface of these sickle red blood cells, the overexpressed protein Lutheran strongly interacts with the Laminin 511/521. The aim of this study is to identify a PPI inhibitor with a high probability of binding to Lutheran for the inhibition of the Lutheran-Laminin 511/521 interaction.
A virtual screening was performed with 395 601 compounds that target Lutheran. Prior validation of a robust docking and scoring protocol was considered on the protein CD80 because this protein has a binding site with similar topological and physico-chemical characteristics and it also has a series of ligands with known affinity constants. This protocol consisted of multiple filtering steps based on docked scores, molecular dynamics simulations, post-screening scores, and molecular properties.
A robust docking and scoring protocol was validated on the protein CD80 with the docking program DOCK6 and the secondary scoring function XSCORE. We identified four molecules for Lutheran that have good structural and physico-chemical properties.
We took advantage of the similarities between the binding site of Lutheran and that of the protein CD80 to set up a robust docking and scoring protocol. Our protocol for primary scoring filtering, molecular dynamics simulation filtering, secondary scoring filtering, and molecular property filtering allows discarding most of the ligands with four compounds that are promising candidates for inhibiting the Lutheran-Laminin 511/521 interaction.
镰状细胞贫血是一种遗传性血液疾病，其特征是红细胞呈现异常、僵硬的镰刀状。在镰状细胞病血管闭塞性危机的发病机制中，红细胞与内皮细胞结合并促进血管闭塞。在这些镰状红细胞表面，过表达的路德蛋白与层粘连蛋白511/521强烈相互作用。本研究的目的是鉴定一种极有可能与路德蛋白结合的蛋白质-蛋白质相互作用（PPI）抑制剂，以抑制路德蛋白-层粘连蛋白511/521的相互作用。
对395601种靶向路德蛋白的化合物进行虚拟筛选。由于蛋白质CD80具有拓扑和物理化学特性相似的结合位点，并且有一系列已知亲和常数的配体，因此在蛋白质CD80上对稳健的对接和评分方案进行了预先验证。该方案包括基于对接分数、分子动力学模拟、筛选后分数和分子性质的多个过滤步骤。
使用对接程序DOCK6和二级评分函数XSCORE在蛋白质CD80上验证了稳健的对接和评分方案。我们鉴定出四种针对路德蛋白的分子，它们具有良好的结构和物理化学性质。
我们利用路德蛋白和蛋白质CD80结合位点之间的相似性建立了一个稳健的对接和评分方案。我们的一级评分过滤、分子动力学模拟过滤、二级评分过滤和分子性质过滤方案允许舍弃大多数配体，留下四种有望抑制路德蛋白-层粘连蛋白511/521相互作用的化合物。
