Deciphering the Shared and Specific Drug Resistance Mechanisms of Anaplastic Lymphoma Kinase via Binding Free Energy Computation  

作　　者：Yang Yu Zhe Wang Lingling Wang Qinghua Wang Rongfan Tang Sutong Xiang Qirui Deng Tingjun Hou Huiyong Sun 

机构地区：[1]Department of Medicinal Chemistry,China Pharmaceutical University,Nanjing 210009,Jiangsu,P.R.China [2]Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,Zhejiang,P.R.China

出　　处：《Research》2024年第1期663-674,共12页研究（英文）

基　　金：the National Key R&D Program of China(2021YFE0206400);the National Natural Science Foundation of China(81603031);the Natural Science Foundation of Zhejiang Province(LQ21H300007);the Young Elite Scientists Sponsorship Program by CPU(131810011 and 1132010013).

摘　　要：Anaplastic lymphoma kinase(ALK),a tyrosine receptor kinase,has been proven to be associated with the occurrence of numerous malignancies.Although there have been already at least 3 generations of ALK inhibitors approved by FDA or in clinical trials,the occurrence of various mutations seriously attenuates the effectiveness of the drugs.Unfortunately,most of the drug resistance mechanisms still remain obscure.Therefore,it is necessary to reveal the bottom reasons of the drug resistance mechanisms caused by the mutations.In this work,on the basis of verifying the accuracy of 2 main kinds of binding free energy calculation methodologies[end-point method of Molecular Mechanics with Poisson-Boltzmann/Generalized Born and Surface Area(MM/PB(GB)SA)and alchemical method of Thermodynamic Integration(TI)],we performed a systematic analysis on the ALK systems to explore the underlying shared and specific drug resistance mechanisms,covering the one-drug-multiple-mutation and multiple-drug-onemutation cases.

关 键 词：DRUGS ANAPLASTIC CLINICAL 

分 类 号：R733.4[医药卫生—肿瘤]