Discovery of new small-molecule cyclin-dependent kinase 6 inhibitors through computational approaches.

Excessive cell proliferation due to cell cycle disorders is one of the hallmarks of breast cancer. Cyclin-dependent kinases (CDKs), which are involved in the transition of the cell cycle from G1 phase to S phase by combining CDKs with cyclin, are considered promising targets with broad therapeutic potential based on their critical role in cell cycle regulation. Pharmacological evidence has shown that abnormal cell cycle due to the overexpression of CDK6 is responsible for the hyperproliferation of cancer cells. Blocking CDK6 expression inhibits tumour survival and growth. Therefore, CDK6 can be regarded as a potential target for anticancer therapeutics. Thus, small molecules that can be considered CDK inhibitors have been developed into promising anticancer drugs. In this study, combined structure-based and ligand-based in silicon models were created to identify new chemical entities against CDK6 with the appropriate pharmacokinetic properties. The database used to screen drug-like compounds in this thesis was based on the best E-pharmacophore hypothesis and the best ligand-based drug hypothesis. As a result, 147 common compounds were identified by further molecular docking. Surprisingly, the in vitro evaluation results of 20 of those compounds showed that the two had good CDK6 inhibitory effects. The best compound was subjected to kinase panel screening, followed by molecular dynamic simulations. The 50-ns MD studies revealed the pivotal role of VAL101 in the binding of inhibitors to CDK6. Overall, the identification of two new chemical entities with CDK6 inhibitory activity demonstrated the feasibility and potential of the new method.

A bioinformatics investigation into molecular mechanism of Yinzhihuang granules for treating hepatitis B by network pharmacology and molecular docking verification.

Yinzhihuang granules (YZHG) is a patented Chinese medicine for the treatment of hepatitis B. This study aimed to investigate the intrinsic mechanisms of YZHG in the treatment of hepatitis B and to provide new evidence and insights for its clinical application. The chemical compounds of YZHG were searched in the CNKI and PUBMED databases, and their putative targets were then predicted through a search of the SuperPred and Swiss Target Prediction databases. In addition, the targets of hepatitis B were obtained from TTD, PharmGKB and DisGeNET. The abovementioned data were visualized using Cytoscape 3.7.1, and network construction identified a total of 13 potential targets of YZHG in the treatment of hepatitis B. Molecular docking verification showed that CDK6, CDK2, TP53 and BRCA1 might be strongly correlated with hepatitis B treatment. Furthermore, GO and KEGG analyses indicated that the treatment of hepatitis B by YZHG might be related to positive regulation of transcription, positive regulation of gene expression, the hepatitis B pathway and the viral carcinogenesis pathway. Network pharmacology intuitively shows the multicomponent, multitarget and multichannel pharmacological effects of YZHG in the treatment of hepatitis B and provides a scientific basis for its mechanism of action.

Artificial Intelligence Approach to Find Lead Compounds for Treating Tumors.

It has been demonstrated that MMP13 enzyme is related to most cancer cell tumors. The world's largest traditional Chinese medicine database was applied to screen for structure-based drug design and ligand-based drug design. To predict drug activity, machine learning models (Random Forest (RF), AdaBoost Regressor (ABR), Gradient Boosting Regressor (GBR)), and Deep Learning models were utilized to validate the Docking results, and we obtained an R2 of 0.922 on the training set and 0.804 on the test set in the RF algorithm. For the Deep Learning algorithm, R2 of the training set is 0.90, and R2 of the test set is 0.810. However, these TCM compounds fly away during the molecular dynamics (MD) simulation. We seek another method: peptide design. All peptide database were screened by the Docking process. Modification peptides were optimized the interaction modes, and the affinities were assessed with ZDOCK protocol and Refine Docked protein protocol. The 300 ns MD simulation evaluated the stability of receptor-peptide complexes. The double-site effect appeared on S2, a designed peptide based on a known inhibitor, when complexed with BCL2. S3, a designed peptide referred from endogenous inhibitor P16, competed against cyclin when binding with CDK6. The MDM2 inhibitors S5 and S6 were derived from the P53 structure and stable binding with MDM2. A flexible region of peptides S5 and S6 may enhance the binding ability by changing its own conformation, which was unforeseen. These peptides (S2, S3, S5, and S6) are potentially interesting to treat cancer; however, these findings need to be affirmed by biological testing, which will be conducted in the near future.

2-Methylpyridine-1-ium-1-sulfonate as an Inducer of Apoptosis and Cell Cycle Arrest: A comparative in vitro and Computational Study.

"Let food be thy medicine and thy medicine be thy food" was expressed by Hippocrates and the health benefits of medicinal plants and natural products have been considered by humans since historic times. The current study aims to investigate the anti-cancer activity of 2-Methylpyridine-1-ium-1-sulfonate (MPS) isolated from bulbs of Allium hirtifolium. The MPS compound (in a dose-dependent manner) induced arrest the AGS cells in G1 and G2/M phases, and Caco-2 cells in G1 and S phases. These findings were associated with the down-regulation of cyclin D1, CDK4, and up-regulation of p21, p27 and p53. According to the morphological observations and DNA fragmentation assay, the MPS compound induced apoptosis in both cell lines, and also cause a significant increase in the expression of Bax/Bcl-2. In this context, our molecular docking results unveiled that the MPS compound has considerable affinity to interact with the minor groove of ctDNA and also with cell cycle kinases. To approve and find the accurate MPS mode of action against cancer cell lines (especially in gastrointestinal cancer) further studies is highly recommended.