Structural optimization of pyrrolopyrimidine BTK inhibitors based on molecular simulation

作者全名："Wu, Jinping; Li, Peng; Chen, Xiaodie; Liu, Rong; Mu, Yucheng; Shen, Yan; Cheng, Xilan; Shu, Mao; Bai, Yixiao"

作者地址："[Wu, Jinping; Li, Peng; Mu, Yucheng; Bai, Yixiao] Langzhong Peoples Hosp, Pharm Dept, Nanchong, Peoples R China; [Chen, Xiaodie; Liu, Rong; Shen, Yan; Shu, Mao] Chongqing Univ Technol, Sch Pharm & Bioengn, Chongqing, Peoples R China; [Chen, Xiaodie; Liu, Rong; Shen, Yan; Shu, Mao] Chongqing Key Lab Screening & Act Evaluat Targeted, Chongqing, Peoples R China; [Cheng, Xilan] Chongqing Med Univ, Pharm Dept, Affiliated Hosp 1, Chongqing, Peoples R China"

通信作者："Bai, YX (通讯作者)，Langzhong Peoples Hosp, Pharm Dept, Nanchong, Peoples R China."

来源：JOURNAL OF MOLECULAR MODELING

ESI学科分类：CHEMISTRY

WOS号：WOS:001100760700001

JCR分区：Q3

影响因子：2.1

年份：2023

卷号：29

期号：12

开始页：　

结束页：　

文献类型：Article

关键词：BTK inhibitors; Pyrrolopyrimidine derivatives; 3D-QSAR; Molecular docking; Molecular dynamics simulation

摘要："ContextBTK is a critical regulator involved in the proliferation, differentiation, and apoptosis of B cells. BTK inhibitors can effectively alleviate various diseases such as tumors, leukemia, and asthma. During this study, a range of novel BTK inhibitors were designed using 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation.MethodsWe selected 41 pyrrolopyrimidine derivatives as BTK inhibitors to structure a 3D-QSAR model. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were adopted to research the connection between the pharmacological activities and chemical structures of the compounds. The CoMFA model (q2 = 0.519, R2 = 0.971), CoMSIA model (q2 = 0.512, R2 = 0.990), and external validation demonstrated excellent predictive performance and reliability of the 3D-QSAR model. We designed eight novel molecules with higher inhibitory activities according to the three-dimensional equipotential fields and explored the interactions between the compounds and BTK by molecular docking, which showed that the novel molecules had higher binding affinities with BTK than the template molecule 18. Then, the results of molecular docking were further verified by MD simulation, which showed that amino acid residues such as Leu528, Val416, and Met477 played vital parts in the interaction, and the binding free energy analysis showed that the novel molecules had higher stability with BTK. Finally, the ADME/T properties were predicted for all of the novel compounds, and the results showed that the majority of them had favorable pharmacokinetic properties. Therefore, this study provides strong support for the development of novel BTK inhibitors."

基金机构：National Natural Science Foundation of China [82100684]; Sichuan Provincial Hospital Association Youth Pharmacist Research Special Fund Project [22036]

基金资助正文：The National Natural Science Foundation of China (82100684) and the Sichuan Provincial Hospital Association Youth Pharmacist Research Special Fund Project (22036) provided funding for the development of this study.