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. © 2021 Elsevier Inc.