Department of Biotechnology, FBMS&T, Sri Ramachandra Institute of Higher Education and Research (DU), Porur, Chennai, Tamil Nadu, India.
Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India.
Adv Protein Chem Struct Biol. 2023;135:97-124. doi: 10.1016/bs.apcsb.2023.01.003. Epub 2023 Mar 11.
Cyclin-dependent kinase 6 (CDK6) is an essential kinase in cell cycle progression, which is a viable target for inhibitors in various malignancies, including breast cancer. This study aimed to virtually screen efficient compounds as new leads in treating breast cancer using a drug repurposing approach. Apoptosis regulatory compounds were taken from the seleckchem database. Molecular docking experiments were carried out in the presence of abemaciclib, a routinely used FDA drug. Compared to conventional drugs, the two compounds demonstrated a higher binding affinity for CDK6. Compounds (N-benzyl-6-[(4-hydroxyphenyl)methyl]-8-(naphthalen-1-ylmethyl)-4,7-dioxo-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide) and (1'-[4-[1-(4-fluorophenyl)indol-3-yl]butyl]spiro[1H-2-benzofuran-3,4'-piperidine]) were discovered to have an inhibitory effect against CDK6 at -8.49 and -6.78kcal/mol, respectively, compared to -8.09kcal/mol of the control molecule, the interacting residues of these two new compounds were found to fall within the binding site of the CDK6 molecule. Both compounds exhibited equal ADME features compared with abemaciclib and would be well distributed and metabolized by the body with an appropriate druglikeness range. Lastly, molecular dynamics was initiated for 200ns for the selected potent inhibitors and abemaciclib as complexed with CDK6. The RMSD, RMSF, Rg, H-Bond interactions, SASA, PCA, FEL, and MM/PBSA analysis were performed for the complexes to assess the stability, fluctuations, radius of gyration, hydrogen bond interaction, solvent accessibility, essential dynamics, free energy landscape, and MM/PBSA. The selected two compounds are small molecules in the appropriate druglikeness range. The results observed in molecular docking and molecular dynamics simulations were most promising for two compounds, suggesting their potent inhibitory effect against CDK6. We propose that these candidate compounds can undergo in vitro validation and in vivo testing for their further use against cancer.
周期蛋白依赖性激酶 6（CDK6）是细胞周期进展中必不可少的激酶，是包括乳腺癌在内的各种恶性肿瘤抑制剂的可行靶点。本研究旨在通过药物再利用方法，虚拟筛选有效化合物作为治疗乳腺癌的新先导。凋亡调节化合物取自 seleckchem 数据库。在阿贝西利（一种常规使用的 FDA 药物）存在的情况下进行分子对接实验。与传统药物相比，这两种化合物对 CDK6 的结合亲和力更高。与对照分子（N-苄基-6-[[4-（4-羟基苯基）甲基]-8-（萘-1-基甲基）-4,7-二氧代-3,6,9,9a-四氢-2H-吡嗪并[1,2-a]嘧啶-1-甲酰胺）相比，化合物（1'-[[4-[1-（4-氟苯基）吲哚-3-基]丁基]螺[1H-2-苯并呋喃-3,4'-哌啶]）对 CDK6 的抑制作用分别为-8.49 和-6.78kcal/mol，而对照分子的抑制作用为-8.09kcal/mol。这两种新化合物的相互作用残基被发现位于 CDK6 分子的结合位点内。与阿贝西利相比，这两种化合物的 ADME 特征相同，并且在体内具有适当的类药性范围，能够很好地分布和代谢。最后，对选定的有效抑制剂和 CDK6 复合物的阿贝西利进行了 200ns 的分子动力学模拟。对复合物进行了 RMSD、RMSF、Rg、氢键相互作用、SASA、PCA、FEL 和 MM/PBSA 分析，以评估其稳定性、波动、回转半径、氢键相互作用、溶剂可及性、基本动力学、自由能景观和 MM/PBSA。所选的两种化合物都是适当类药性范围内的小分子。分子对接和分子动力学模拟的结果对两种化合物最有希望，表明它们对 CDK6 具有很强的抑制作用。我们建议这些候选化合物可以进行体外验证和体内测试，以便进一步用于癌症治疗。
