title: Exploring the structural and functional impact of the ALK F1174L mutation using bioinformatics approach.
abstract: Crizotinib is the most effective and the only drug that has been approved for the treatment of anaplastic lymphoma kinase (ALK)-positive lung cancer. Reports suggest that there is a development of an acquired resistance against crizotinib action due to the emergence of several mutations in the ALK gene and F1174L is one such mutation. In this study, we used molecular docking and molecular dynamics (MD) approach to decipher the effect of F1174L mutation in drug-target binding. Docking results suggest that crizotinib was found to adopt the most promising conformations to the native-type ALK by identifying the M1199 residue as a prospective partner for making a hydrogen bond as compared to the mutant-type ALK. MD results showed that the average atom, especially atoms of the native-type ALK-crizotinib complex, movements were less, displayed less fluctuation, fast convergence of energy, and changes in geometry. This shows the stable binding of crizotinib with the native-type ALK in comparison to the mutant-type ALK. We believe that this study could be useful for the logical design of stronger, more selective, and more consistent ALK inhibitor against drug-resistant F1174L mutation.
authors: Industrial Biotechnology Division, School of Bio Sciences and Technology, VIT University, Vellore, 632014, Tamil Nadu, India.
authors: Anish
authors: A
authors: Kumar
authors: K
authors: K
authors: Ramanathan
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D001665:Binding Sites; D019295:Computational Biology; D017076:Computer-Aided Design; D000077547:Crizotinib; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005838:Genotype; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases