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Structural basis for drug resistance mechanisms against anaplastic lymphoma kinase
Author(s) -
Goyal Sukriti,
Jamal Salma,
Shanker Asheesh,
Grover Abhinav
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.27437
Subject(s) - anaplastic lymphoma kinase , crizotinib , ceritinib , drug resistance , drug , alk inhibitor , mutation , resistance mutation , kinase , cancer research , pharmacology , biology , medicine , biochemistry , genetics , oncology , gene , reverse transcriptase , rna , malignant pleural effusion , lung cancer
Drug resistance to anaplastic lymphoma kinase (ALK) inhibitors (crizotinib and ceritinib) is caused by mutation in the region encoding kinase domain of ALK. Compounds with potential ability to inhibit all strains of ALK are a solution to tackle the problem of drug resistance. In this study, we delineated positions of residues possessing the ability to make ALK drug resistant upon mutation by assessing them using five parameters (conservation index, binding‐site root‐mean‐square deviation, protein structure stability, change in ATP, and drug‐binding affinity). Four residual positions (Leu 1122, Thr 1151, Phe 1245, and Gly 1269) were ascertained. This study will be beneficial for designing drugs with better proficiency against ALK and the issues of drug resistance. This study can be taken as a pipeline for investigating drug‐resistant mutations in other diseases as well.