Molecular Dynamics Mechanisms of the Inhibitory Effects of Abemaciclib, Hymenialdisine, and Indirubin on CDK-6

Author(s): Gholam Basati, Javad Saffari-Chaleshtori, Saber Abbaszadeh, Majid Asadi-Samani, Korosh Ashrafi-Dehkordi*

Journal Name: Current Drug Research Reviews
(Formerly Current Drug Abuse Reviews)

Volume 11 , Issue 2 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Cyclin-Dependent Kinases-6 (CDK-6) is a serine/threonine protein kinase with regular activity in the cell cycle. Some inhibitors, such as abemaciclib, hymenialdisine, and indirubin, cause cell arrest by decreasing its activity.

Objectives: The purpose of this study was to evaluate the Molecular Dynamic (MD) effects of abemaciclib, hymenialdisine, and indirubin on the structure of CDK-6.

Methods: The PDB file of CDK-6 was obtained from the Protein Data Bank ( After the simulation of CDK-6 in the Gromacs software, 200 stages of molecular docking were run on CDK-6 in the presence of the inhibitors using AutoDock 4.2. The simulation of CDK-6 in the presence of inhibitors was performed after docking.

Results: Abemaciclib showed the greatest tendency to bind CDK-6 via binding 16 residues in the binding site with hydrogen bonds and hydrophobic bonding. CDK-6 docked to hymenialdisine and indirubin increased the Total Energy (TE) and decreased the radius of gyration (Rg). CDK-6 docked to hymenialdisine significantly decreased the coil secondary structure.

Conclusion: CDK-6 is inhibited via high binding affinity to abemaciclib, hymenialdisine, and indirubin inhibitors and induces variation in the secondary structure and Rg in the CDK-6 docked to the three inhibitors. It seems that developing a drug with a binding tendency to CDK6 that is similar to those of abemaciclib, indirubin, and hymenialdisine can change the secondary structure of CDK6, possibly more potently, and can be used to develop anticancer drugs. However, additional studies are needed to confirm this argument.

Keywords: CDK-6, inhibitors, molecular dynamic, simulation, total energy, abemaciclib, protein data bank.

Zachleder V, Ivanov I, Vítová M, Bišová KJ. Effects of cyclin-dependent kinase activity on the coordination of growth and the cell cycle in green algae at different temperatures. Exp Bot 2019; 70(3): 845-58.
[] [PMID: 30395238]
Xiong Y, Li T, Assani G, et al. Ribociclib, a selective cyclin D kinase 4/6 inhibitor, inhibits proliferation and induces apoptosis of human cervical cancer in vitro and in vivo. Biomed Pharmacother 2019.112108602
[] [PMID: 30784916]
Cui J, Qu Z, Harata-Lee Y, et al. Cell cycle, energy metabolism and DNA repair pathways in cancer cells are suppressed by Compound Kushen Injection. BMC Cancer 2019; 19(1): 103.
[] [PMID: 30678652]
Chiang SR, Lin CS, Lin HH, Shieh PC, Kao SH. Bergapten induces G1 arrest of non-small cell lung cancer cells, associated with the p53-mediated cascade. Mol Med Rep 2019; 19(3): 1972-8.
[] [PMID: 30628674]
Dowdy SF. Death of a Dogma: Cyclin D activates Rb by Mono-phosphorylation ind-type Cyclins and Cancer. Cham: Springer 2018; pp. 133-47.
Bortolozzi R, Mattiuzzo E, Trentin L, Accordi B, Basso G, Viola G. Ribociclib, a CDK4/CDK6 kinase inhibitor, enhances glucocorticoid sensitivity in B-acute lymphoblastic leukemia (B-All). Biochem Pharmacol 2018; 153: 230-41.
[] [PMID: 29408328]
Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: A review of regulation, deregulation and therapeutic targets in The cancer. Cell Prolif 2003; 36(3): 131-49.
[] [PMID: 12814430]
Hurvitz S, Martin M, Press M, et al. Treatment with abemaciclib modulates the immune response in gene expression analysis of the neomonarch neoadjuvant study of abemaciclib in postmenopausal women with HR+, HER2 negative breast cancer. San Antonio Breast Cancer Symposium. December 4-8, 2018; San Antonio, Texas.
Corona SP, Generali D. Abemaciclib: A CDK4/6 inhibitor for the treatment of HR+/HER2- advanced breast cancer. Drug Des Devel Ther 2018; 12: 321-30.
[] [PMID: 29497278]
Nguyen DT, Truong GN, Van Vuong T, et al. Synthesis of new indirubin derivatives and their in vitro anticancer activity. Chem Pap 2019; 73: 1083-92.
Wang Y, Hoi PM, Chan JY, Lee SM. New perspective on the dual functions of indirubins in cancer therapy and neuroprotection. Anticancer Agents Med Chem 2014; 14(9): 1213-9.
[] [PMID: 25175685]
Sánchez-Martínez C, Gelbert LM, Lallena MJ, de Dios A. Cyclin Dependent Kinase (CDK) inhibitors as anticancer drugs. Bioorg Med Chem Lett 2015; 25(17): 3420-35.
[] [PMID: 26115571]
Saffari-Chaleshtori J, Shafiee SM, Ghatreh-Samani K, Jalilian N. The study of drug resistance properties of ABCG2 (ATP-binding cassette G2) in contact with thymoquinone, gallic acid, and hesperetin antioxidants. J Herbmed Pharmacol 2019; 8(2): 108-13.
Morris GM, Goodsell DS, Halliday RS, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998; 19(14): 1639-62.
Saffari Chaleshtori J, Heidari Soureshjani E, Reisi F, et al. Damage intensity of carvacrol on prostatic cancer cells linedu145 and molecular dynamic simulation of it effect on apoptotic factors. Int J Pharm Tech Res 2016; 9(6): 261-73.
Saffari-Chaleshtori J, Heidari-Sureshjani E, Moradi F, Jazi HM, Heidarian E. The study of apoptosis-inducing effects of three pre-apoptotic factors by gallic acid, using simulation analysis and the comet assay technique on the prostatic cancer cell line PC3. Malays J Med Sci 2017; 24(4): 18-29.
[] [PMID: 28951686]
Saffari-Chaleshtori J, Heidari-Sureshjani E, Moradi F, Heidarian E. The effects of Thymoquinone on viability and anti-apoptotic factors (BCL-XL, BCL-2, MCL-1) in prostate cancer (PC3) cells, An in vitro and computer-simulated environment study. Adv Pharm Bull 2019; 9(3): 490-6.
Iriyama N, Hino H, Moriya S, et al. The cyclin-dependent kinase 4/6 inhibitor, abemaciclib, exerts dose-dependent cytostatic and cytocidal effects and induces autophagy in multiple myeloma cells. Leuk Lymphoma 2018; 59(6): 1439-50.
[] [PMID: 28918692]
Palumbo A, Lau G, Saraceni M. Abemaciclib, the newest CDK4/6 inhibitor for the treatment of breast cancer. Ann Pharmacother 2019; 53(2): 178-85.
[] [PMID: 30099886]
Meijer L, Thunnissen AM, White AW, et al. Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by hymenialdisine, a marine sponge constituent. Chem Biol 2000; 7(1): 51-63.
[] [PMID: 10662688]
Cheng W, Yang Z, Wang S, et al. Recent development of CDK inhibitors: An overview of CDK/inhibitor co-crystal structures. Eur J Med Chem 2019; 164: 615-39.
[] [PMID: 30639897]
Carugo O, Pongor S. A normalized root-mean-square distance for comparing protein three-dimensional structures. Protein Sci 2001; 10(7)
[] [PMID: 11420449]
Lobanov MY, Bogatyreva N, Galzitskaya O. Radius of gyration as an indicator of protein structure compactness. Mol Biol 2008; 42(4): 623-8.
[] [PMID: 18856071]

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 18 October, 2019
Page: [135 - 141]
Pages: 7
DOI: 10.2174/2589977511666191018180001

Article Metrics

PDF: 22