School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
Adv Protein Chem Struct Biol. 2021;123:49-71. doi: 10.1016/bs.apcsb.2020.10.001. Epub 2020 Dec 4.
Membrane proteins are the most common types of cancer that are active in the prognosis. Membrane proteins are a distinguishing characteristic of a cancer cell. In tumor cell therapy, the overexpressed membrane proteins are becoming ever more relevant. The 3-kinase (PI3K)/AKT phosphatidylinositol pathway is downstream triggered by different extracellular signals, and this signaling pathway activation impacts a variety of proliferation of the cellular processes like cell growth and surviving. Frequent PI3K/AKT dysregulation in human cancer has rendered proteins of this pathway desirable for diagnostic markers. Members of the ERBB family-like ERBB2 and ERBB3 activate intracellular signaling pathways such as PI3K/AKT. The mutations in these proteins dysfunctions the proteins in the downstream. Considering this importance, we have developed a computational pipeline to identify the mutation position with a highest number of mutations and to screen them for pathogenicity, stability, conservation, and structural changes using PredictSNP, iStable, ConSurf, and GROMACS simulation software respectively. Further, a virtual screening approach was initiated to find the most similar non-toxic lead compound, which could be an alternative to the currently used lapatinib. To conclude, protein-ligand dynamics were undertaken to study the actions of native and mutants with the lapatinib and the lead compound. From the overall analysis, we identified position 755 with leucine in the native condition is prone to frequent mutations. The leucine at 755th position is more prone to mutate as serine and tryptophan. Further from the computational analysis, we identified that the mutation L755S is more significant than the L755W mutation. We have witnessed CID140590176 be a potential lead compound with no toxicity. The behavior of the lead compound has shown more compactness with an increased number of intermolecular hydrogen bonds in the ERBB2 with L755S. This lead compound can be further taken for experimental validations, and we believe that this lead compound could be a potent ERBB2 inhibitor.
膜蛋白是最常见的活跃于预后的癌症类型。膜蛋白是癌细胞的一个显著特征。在肿瘤细胞治疗中，过度表达的膜蛋白变得越来越重要。3-激酶（PI3K）/AKT 磷脂酰肌醇途径是由不同的细胞外信号触发的下游途径，这种信号通路的激活影响了多种细胞增殖过程，如细胞生长和存活。人类癌症中频繁的 PI3K/AKT 失调使得该途径的蛋白成为理想的诊断标志物。ERBB 家族成员如 ERBB2 和 ERBB3 激活细胞内信号通路，如 PI3K/AKT。这些蛋白的突变会使下游蛋白功能失调。考虑到这一点的重要性，我们开发了一种计算管道，以识别突变位置，该位置的突变数量最多，并使用 PredictSNP、iStable、ConSurf 和 GROMACS 模拟软件分别对其进行致病性、稳定性、保守性和结构变化的筛选。此外，还启动了虚拟筛选方法，以找到最相似的无毒先导化合物，该化合物可能替代目前使用的拉帕替尼。总之，进行了蛋白质-配体动力学研究，以研究天然和突变体与拉帕替尼和先导化合物的作用。从整体分析中，我们发现天然条件下第 755 位的亮氨酸容易频繁突变。第 755 位的亮氨酸更容易突变为丝氨酸和色氨酸。从计算分析进一步发现，L755S 突变比 L755W 突变更显著。我们已经观察到 CID140590176 是一种无毒的潜在先导化合物。先导化合物的行为表现出更高的紧凑性，与 L755S 的 ERBB2 中的分子间氢键数量增加。该先导化合物可进一步进行实验验证，我们相信该先导化合物可能是一种有效的 ERBB2 抑制剂。
