Singh P K, Silakari O
a Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research , Punjabi University , Patiala , Punjab , India.
SAR QSAR Environ Res. 2017 Mar;28(3):221-233. doi: 10.1080/1062936X.2017.1300189. Epub 2017 Mar 14.
Extensively validated 3D pharmacophore models for ALK (anaplastic lymphoma kinase) and EGFR (T790M) (epithelial growth factor receptor with acquired secondary mutation) were developed. The pharmacophore model for ALK (r = 0.96, q = 0.692) suggested that two hydrogen bond acceptors and three hydrophobic groups arranged in 3-D space are essential for the binding affinity of ALK inhibitors. Similarly, the pharmacophore model for EGFR (T790M) (r = 0.92, q = 0.72) suggested that the presence of a hydrogen bond acceptor, two hydrogen bond donors and a hydrophobic group plays vital role in binding of an inhibitor of EGFR (T790M). These pharmacophore models allowed searches for novel ALK and EGFR (T790M) dual inhibitors from multiconformer 3D databases (Asinex, Chembridge and Maybridge). Finally, the eight best hits were selected for molecular dynamics simulation, to study the stability of their complexes with both proteins and final binding orientations of these molecules. After molecular dynamics simulations, one hit has been predicted to possess good binding affinity for both ALK and EGFR (T790M), which can be further investigated for its experimental in-vitro/in-vivo activities.
开发了针对间变性淋巴瘤激酶（ALK）和表皮生长因子受体（T790M）（获得性继发性突变的表皮生长因子受体）的经过广泛验证的3D药效团模型。ALK的药效团模型（r = 0.96，q = 0.692）表明，三维空间中排列的两个氢键受体和三个疏水基团对ALK抑制剂的结合亲和力至关重要。同样，EGFR（T790M）的药效团模型（r = 0.92，q = 0.72）表明，氢键受体、两个氢键供体和一个疏水基团的存在在EGFR（T790M）抑制剂的结合中起着至关重要的作用。这些药效团模型允许从多构象3D数据库（Asinex、Chembridge和Maybridge）中搜索新型ALK和EGFR（T790M）双重抑制剂。最后，选择八个最佳命中物进行分子动力学模拟，以研究它们与两种蛋白质的复合物的稳定性以及这些分子的最终结合取向。经过分子动力学模拟，预测有一个命中物对ALK和EGFR（T790M）都具有良好的结合亲和力，可对其体外/体内实验活性进行进一步研究。
