Two Birds with One Stone: Targeting Wild Type and Drug Resistant Mutant ALK Using Brute Force Screening, MD Simulation and NCI.

Anaplastic lymphoma kinase (ALK) belongs to the class of receptor tyrosine kinase (RTK) subfamily of enzymes which plays a crucial role in cell proliferation, and differentiation, however aberrant expression of ALK results in malignancies such as anaplastic large cell lymphoma (ALCL), and non-small cell lung cancer (NSCLC). Emergence of ALK mutants, especially G1202R variant makes it difficult to treat the disease due to drug resistance. In this study, the atomic level interactions between wild type and G1202R mutant of ALK protein with potential inhibitors have been analysed from MD simulation trajectories in order to identify a potential set of molecules that can successfully inhibit both wild type and mutant ALK - thus omitting the need for designing individual inhibitors for each. The protein-drug interaction was subjected to non-covalent interaction (NCI) analysis using the promolecular densities and reduced density gradients from the promolecular densities of the protein-ligand complex. The analysis reveals the (3-dimensional) regions in real space associated with H-bonding, van der Waals interaction, and steric hindrance in between the ligand and protein molecules. Qualitative analysis indicates that 82 - 85% of the non-covalent interactions are van der Waals forces, 10 - 12% H-bonding, and 3 - 5% steric repulsion. The binding free energy of protein-drug interaction was calculated using MM-PBSA based method. The analysis focused on identifying the skeleton of potential leads that could inhibit both the wild-type and drug-resistant mutant (G1202R) ALK protein.