首页|Deciphering the Shared and Specific Drug Resistance Mechanisms of Anaplastic Lymphoma Kinase via Binding Free Energy Computation
Deciphering the Shared and Specific Drug Resistance Mechanisms of Anaplastic Lymphoma Kinase via Binding Free Energy Computation
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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-one-mutation cases.Through conventional molecular dynamics(cMD)simulation in conjunction with MM/PB(GB)SA and umbrella sampling(US)in conjunction with contact network analysis(CNA),the resistance mechanisms of the in-pocket,out-pocket,and multiple-site mutations were revealed.Especially for the out-pocket mutation,a possible transfer chain of the mutation effect was revealed,and the reason why different drugs exhibited various sensitivities to the same mutation was also uncovered.The proposed mechanisms may be prevalent in various drug resistance cases.
Yang Yu、Zhe Wang、Lingling Wang、Qinghua Wang、Rongfan Tang、Sutong Xiang、Qirui Deng、Tingjun Hou、Huiyong Sun
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Department of Medicinal Chemistry,China Pharmaceutical University,Nanjing 210009,Jiangsu,P.R.China
Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,Zhejiang,P.R.China
国家重点研发计划国家自然科学基金浙江省自然科学基金Young Elite Scientists Sponsorship Program by CPUYoung Elite Scientists Sponsorship Program by CPU
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