Synthesis, biological profile and computational insights of new derivatives of benzo [B][1,4] diazepines as prospective anticancer agents for inhibiting the CDK-2 protein.

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  • Additional Information
    • Publication Information:
      Ahead of Print
    • Source:
      Publisher: Taylor & Francis Country of Publication: England NLM ID: 8404176 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-0254 (Electronic) Linking ISSN: 07391102 NLM ISO Abbreviation: J Biomol Struct Dyn Subsets: MEDLINE
    • Publication Information:
      Publication: June 2012- : Oxon, UK : Taylor & Francis
      Original Publication: Guilderland, NY : Adenine Press, [c1983-
    • Abstract:
      In the current work, a new series of benzo[b][1, 4] diazepines ( A-1 to C-4) was synthesized and screened against three different human cancer cell lines, HepG2 (hepatocellular carcinoma), HeLa (cervical cancer) and MCF-7 (breast cancer), by employing MTT (MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay. The outcomes of in vitro screening revealed that all the compounds exhibited momentous anticancer activity, most notably against the MCF-7 cell line by B1-4 compounds. Further, network pharmacology, UALCAN analysis, molecular docking, molecular dynamics (MD) simulations and density functional theory calculations were conducted to explore expression analysis, pharmacokinetics, toxicity profiles and binding interactions of the B1-4 compounds. By UALCAN, we explored the expression analysis of CDK-2 in 19 cancers. Through UALCAN, Pan-cancer analysis revealed that the expression of CDK-2 in 19 cancers was statistically significant. Among the 19 cancers, the CDK-2 expression was significantly upregulated in breast cancer (BRCA), cervical cancer (CESC) and lung carcinoma (LUSC) than normal tissues. Enzyme-docking examination revealed that B1-4 compounds exhibited significant binding affinity against the CDK-2 (PDB ID: 5IEV) drug target protein. Furthermore, MD simulations supported the docking results, which confirmed that the ligand + protein complex was in a stable conformation throughout the simulation time of 100 nanoseconds. Therefore, the present study demonstrates the potential of these benzo [b][1,4] diazepines as promising drug candidates against cancer.Communicated by Ramaswamy H. Sarma.
    • Contributed Indexing:
      Keywords: ADMET screening; DFT analysis and anticancer activity; MD simulation; anticancer agent; benzodiazepine; molecular docking
      Local Abstract: [plain-language-summary] A new series of benzodiazepine molecules were designed and synthesized as CDK-2 inhibitors. In vitro anticancer potential against HepG2, HeLa and MCF-7 cancer cells were assessed.Network pharmacology; expression analysis; in silico docking; molecular dynamics simulation; molecular mechanics–generalized Born and surface area; and absorption, distribution, metabolism, excretion and toxicity studies were carried out.This study overall revealed the anticancer activity of benzodiazepines by integrating network pharmacology, molecular modeling and in vitro experiments.
    • Publication Date:
      Date Created: 20240212 Latest Revision: 20240212
    • Publication Date:
      20240213
    • Accession Number:
      10.1080/07391102.2024.2314270
    • Accession Number:
      38344942