Most of the available crystal structures of epidermal growth factor receptor (EGFR) kinase domain, bound to drug inhibitors, originated from ligand-based drug design studies. Here, we used variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. The families shared similar mutational profiles and similarity in the ligand R-groups (chemical composition, geometry, and charge) facing the C-helix, mutation sites, and DFG domain. For structure-based drug design, we recommend a systematic decision-making process for choice of template, guided by appropriate pairwise fitting and clustering before the molecular docking step. Alternatively, the binding site shape/volume can be used to filter and select the compound libraries.

大多数与药物抑制剂结合的表皮生长因子受体 (EGFR) 激酶域的可用晶体结构源自基于配体的药物设计研究。在这里，我们使用 110 种晶体结构的变化来组装八个不同的家族，突出了 EGFR 激酶域 N 叶中的 C 螺旋方向。这些家族在面对 C 螺旋、突变位点和 DFG 结构域的配体 R 组（化学组成、几何结构和电荷）方面具有相似的突变谱和相似性。对于基于结构的药物设计，我们建议在分子对接步骤之前通过适当的成对拟合和聚类指导模板选择的系统决策过程。或者，结合位点形状/体积可用于过滤和选择化合物库。