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

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

Highlights

• 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.

Keywords:

• benzodiazepine
• anticancer agent
• molecular docking
• MD simulation
• ADMET screening
• DFT analysis and anticancer activity

Acknowledgement

The authors are highly thankful and acknowledge gratefully to SERB-DST, India for providing financial assistance from the Core Research Grant Project with file number CRG/2022/000838. The authors also extend their appreciation to the Deanship of Scientific Research, King Khalid University, Abha, Saudi Arabia, for providing financial support under Grant No.RGP.1/304/44.

CRediT authorship contribution statement

Parvaiz A. Dar: synthesis, characterization, methodology, writing original draft and formal analysis. Basharat A. Bhat: molecular docking, in vitro anticancer activity, free energy landscape (FEL), DFT analysis, expression analysis, writing original draft and formal analysis. Mushtaq A. Mir: review and editing. Somdatta Yashwant Chaudhari: MD simulation analysis. Wajaht A. Shah: concept and supervision.

Disclosure statement

There is no conflict of interest to declare.

Data availability statement

Data will be made available on request.

Additional information

Funding

The authors are highly thankful and acknowledge gratefully to SERB-DST, India for providing financial assistance from the Core Research Grant Project with file number CRG/2022/000838. The authors also extend their appreciation to the Deanship of Scientific Research, King Khalid University, Abha, Saudi Arabia, for providing financial support under Grant No.RGP.1/304/44.