"Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation"

作者全名："Zhou, Yanting; Li, Xiandeng; Luo, Peifang; Chen, Huiting; Zhou, Yan; Zheng, Xueting; Yin, Yuan; Wei, Haoche; Liu, Hongji; Xia, Wen; Shi, Mingsong; Li, Xiaoan"

作者地址："[Zhou, Yanting; Xia, Wen] Zunyi Med Univ, Minist Educ, Key Lab Basic Pharmacol, Zunyi, Guizhou, Peoples R China; [Zhou, Yanting; Xia, Wen] Zunyi Med Univ, Minist Educ, Joint Int Res Lab Ethnocentr, Zunyi, Guizhou, Peoples R China; [Li, Xiandeng; Chen, Huiting] Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China; [Luo, Peifang] Zunyi Med Univ, Affiliated Hosp, Dept Cardiovasc Surg, Zunyi, Guizhou, Peoples R China; [Zhou, Yan; Zheng, Xueting; Yin, Yuan; Shi, Mingsong; Li, Xiaoan] Univ Elect Sci & Technol China, Mianyang Cent Hosp, Sch Med, NHC Key Lab Nucl Technol Med Transformat, Mianyang, Sichuan, Peoples R China; [Wei, Haoche] Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, State Key Lab Biotherapy, Chengdu, Sichuan, Peoples R China; [Wei, Haoche] Sichuan Univ, West China Hosp, Canc Ctr, Chengdu, Sichuan, Peoples R China; [Liu, Hongji] Univ Elect Sci & Technol China, Mianyang Cent Hosp, Sch Med, Dept Ophthalmol, Mianyang, Sichuan, Peoples R China"

通信作者："Xia, W (通讯作者)，Zunyi Med Univ, Minist Educ, Key Lab Basic Pharmacol, Zunyi, Guizhou, Peoples R China.; Xia, W (通讯作者)，Zunyi Med Univ, Minist Educ, Joint Int Res Lab Ethnocentr, Zunyi, Guizhou, Peoples R China.; Shi, MS (通讯作者)，Univ Elect Sci & Technol China, Mianyang Cent Hosp, Sch Med, NHC Key Lab Nucl Technol Med Transformat, Mianyang, Sichuan, Peoples R China."

来源：FRONTIERS IN PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001000433200001

JCR分区：Q1

影响因子：4.4

年份：2023

卷号：14

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：abemaciclib; cyclin-dependent kinase 4; cyclin-dependent kinase 6; inhibitor; molecular dynamics simulation; binding free energy

摘要："CDK4/6 plays a crucial role in various cancers and is an effective anticancer drug target. However, the gap between clinical requirements and approved CDK4/6 drugs is unresolved. Thus, there is an urgent need to develop selective and oral CDK4/6 inhibitors, particularly for monotherapy. Here, we studied the interaction between abemaciclib and human CDK6 using molecular dynamics simulations, binding free energy calculations, and energy decomposition. V101 and H100 formed stable hydrogen bonds with the amine-pyrimidine group, and K43 interacted with the imidazole ring via an unstable hydrogen bond. Meanwhile, I19, V27, A41, and L152 interacted with abemaciclib through p-alkyl interactions. Based on the binding model, abemaciclib was divided into four regions. With one region modification, 43 compounds were designed and evaluated using molecular docking. From each region, three favorable groups were selected and combined with each other to obtain 81 compounds. Among them, C2231-A, which was obtained by removing the methylene group from C2231, showed better inhibition than C2231. Kinase profiling revealed that C2231-A showed inhibitory activity similar to that of abemaciclib; additionally, C2231-A inhibited the growth of MDA-MB-231 cells to a greater extent than did abemaciclib. Based on molecular dynamics simulation, C2231-A was identified as a promising candidate compound with considerable inhibitory effects on human breast cancer cell lines."

基金机构："Natural Science Foundation of Sichuan, China [2022NSFSC1467]; National Natural Science Foundation of China [22203056]; Science and Technology Planning Project of Sichuan Province [2021YJ0483]; NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital) [2022HYX001, 2022HYX005]; Postdoctoral Interdisciplinary Innovation Fund of Sichuan University [ghfund202302022385]"

基金资助正文："The present work was supported by Natural Science Foundation of Sichuan, China (No. 2022NSFSC1467), the National Natural Science Foundation of China (No. 22203056), the Science and Technology Planning Project of Sichuan Province (No. 2021YJ0483), NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital) (Nos 2022HYX001 and 2022HYX005), GHfund B (ghfund202302022385), and the Postdoctoral Interdisciplinary Innovation Fund of Sichuan University."