Molecular Dynamics Validation of Crizotinib Resistance to ALK Mutations (L1196M and G1269A) and Identification of Specific Inhibitors.
Anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients are mostly treated with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first generation ALK inhibitor practiced as a primary chemo to combat cancer cells followed by second generation inhibitor ceritinib which are effective against crizotinib resistant ALK mutations. However, patients treated with these drugs invariably relapsed because of the development of new drug resistance mutations. In this study we explored the crizotinib resistance in the presence of ALK mutations L1196M and G1269A through molecular dynamics simulation studies. Further mutation specific inhibitors CID 71748211 and CID 71728095 were identified to potentially inhibit ALK with mutations L1196M and G1269A, respectively. This computational investigation in-sighted the molecular factors involved in crizotinib resistance which enhanced in the identification of new ALK drugs that brings individualized medicine to treat ALK positive NSCLC patients with specific mutations. J. Cell. Biochem. 118: 3462-3471, 2017. © 2017 Wiley Periodicals, Inc.
Molecular and Nanomedicne Research Unit, Centre for Nanoscience and Nanotechnology, Sathyabama University, Jeppiaar Nagar, Chennai 600119, Tamil Nadu, India.
Nagarajan
N
Nagasundaram
Molecular and Nanomedicne Research Unit, Centre for Nanoscience and Nanotechnology, Sathyabama University, Jeppiaar Nagar, Chennai 600119, Tamil Nadu, India.
Carlton Ranjith
CR
Wilson Alphonse
Centre for Marine Science and Technology (CMST), Manonmaniam Sundaranar University, Rajakkamangalam, Kanyakumari District 629502, Tamil Nadu, India.
Prakash Vincent
PV
Samuel Gnana
Molecular and Nanomedicne Research Unit, Centre for Nanoscience and Nanotechnology, Sathyabama University, Jeppiaar Nagar, Chennai 600119, Tamil Nadu, India.
Rajesh Kannan
0000-0001-6846-5777
RK
Rajaretinam
D019943:Amino Acid Substitution; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000178:diet therapy / Q000201:enzymology* / Q000235:genetics; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
ALK; CRIZOTINIB; LUNG CANCER; MOLECULAR DOCKING; MOLECULAR DYNAMICS SIMULATION; PERSONALIZED MEDICINE