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

Yanting Zhou; Xiandeng Li; Peifang Luo; Huiting Chen; Yan Zhou; Xueting Zheng; Yuan Yin; Haoche Wei; Hongji Liu; Wen Xia; Mingsong Shi; Xiaoan Li

doi:10.3389/fphar.2023.1154654

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

Front Pharmacol. 2023 May 10:14:1154654. doi: 10.3389/fphar.2023.1154654. eCollection 2023.

Authors

Yanting Zhou¹, Xiandeng Li², Peifang Luo³, Huiting Chen², Yan Zhou⁴, Xueting Zheng⁴, Yuan Yin⁴, Haoche Wei⁵, Hongji Liu⁶, Wen Xia¹, Mingsong Shi⁴, Xiaoan Li⁴

Affiliations

¹ Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China.
² College of Pharmacy, Chongqing Medical University, Chongqing, China.
³ Department of Cardiovascular Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
⁴ NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, Sichuan, China.
⁵ State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
⁶ Department of Ophthalmology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, Sichuan, China.

Abstract

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 π-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.

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

Grants and funding

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.