■描述小分子CSF1R抑制剂在临床开发中对集落刺激因子-1受体(CSF1R)的基于结构的抑制作用,用于靶标识别和癌症治疗中的潜在前导优化,因为CSF1R是一种新型的预测生物标志物用于癌症的免疫治疗。
■化合物在分子操作环境中通过诱导拟合对接方案进行了计算机建模(MOE,妈妈.v.2015).CSF1R激酶的三维(3D)X射线结晶结构(蛋白质数据库,ID4R7H)从结构生物信息学研究实验室(RSCB)蛋白质数据库获得。依地替尼的3D构象,DCC-3014,ARRY-382,BLZ-945,Chiauranib,多替尼,和索拉非尼从PubChem数据库获得。这些结构在Amber10:EHT分子力场中建模,快速制备应用用于校正和优化缺失残基的结构,H计数,终端封顶,和候补。结合位点定义在CSF1R激酶的共结晶配体附近。化合物通过三角形匹配器放置方法进行对接,并通过伦敦dG评分函数进行排名。通过诱导拟合方法进一步细化了对接姿势。在DiscoveryStudioVisualizerv17.2中,使用具有最低结合得分(ΔG)的姿势对配体相互作用谱进行建模。共结晶的配体在其apo构象中对接,并计算均方根偏差以验证对接协议。
■所有7种CSF1R抑制剂均与Met637残基相互作用,表现出选择性,依替尼除外。通过与Asp-Phe-Gly(DFG)基序的Asp797相互作用和/或阻碍Glu633和Lys616之间形成的保守盐桥,从而稳定激活环,或与近膜结构域中的色氨酸残基(Trp550)相互作用。DCC-3014、ARRY-382、BLZ-945和索拉非尼以最低结合能与CSF1R激酶结合。
■嘧啶是与CSF1R残基相互作用的有效抑制剂。DCC-3014和ARRY-382表现出优异的药物潜力,表现出良好的结构稳定性和亲和力。
UNASSIGNED: Delineate structure-based inhibition of colony-stimulating factor-1 receptor (CSF1R) by small molecule CSF1R inhibitors in clinical development for target identification and potential lead optimization in cancer therapeutics since CSF1R is a novel predictive biomarker for immunotherapy in cancer.
UNASSIGNED: Compounds were in silico modelled by induced fit docking protocol in a molecular operating environment (MOE, MOE.v.2015). The 3-dimensional (3D) X-ray crystallized structure of CSF1R kinase (Protein Databank, ID 4R7H) was obtained from Research Collaboratory for Structural Bioinformatics (RSCB) Protein Databank. The 3D conformers of edicotinib, DCC-3014, ARRY-382, BLZ-945, chiauranib, dovitinib, and sorafenib were obtained from PubChem Database. These structures were modelled in Amber10:EHT molecular force field, and quick prep application was used to correct and optimize the structures for missing residues, H-counts, termini capping, and alternates. The binding site was defined within the vicinity of the co-crystallized ligand of CSF1R kinase. The compounds were docked by the triangular matcher placement method and ranked by the London dG scoring function. The docked poses were further refined by the induced fit method. The pose with the lowest binding score (ΔG) was used to model the ligand interaction profile in Discovery Studio Visualizer v17.2. The co-crystallized ligand was docked in its apo conformation, and root-mean-square deviation was computed to validate the docking protocol.
UNASSIGNED: All 7 CSF1R inhibitors interact with residue Met637 exhibiting selectivity except for edicotinib. The inhibitors maintain CSF1R in an auto-inhibitory conformation by interacting with Asp797 of the Asp-Phe-Gly (DFG) motif and/or hindering the conserved salt bridge formed between Glu633 and Lys616 thus stabilizing the activation loop, or interacting with tryptophan residue (Trp550) in the juxtamembrane domain. DCC-3014, ARRY-382, BLZ-945, and sorafenib bind with the lowest binding energy with CSF1R kinase.
UNASSIGNED: Pyrimidines are potent inhibitors that interact with CSF1R residues. DCC-3014 and ARRY-382 exhibit exceptional pharmaceutical potential exhibiting great structural stability and affinity.