Aug 2026· Journal of Receptor and Signal Transduction Research· pp.
1-17
· 0 citations· 28 references
Medicine
TL;DR
This study highlights the usefulness of computational approaches in the discovery of novel isatin-based multi-target lead candidates for cancer therapy and suggests that compound 4 represents a promising lead for further investigation.
Abstract
The isatin scaffold has emerged as a promising platform for the development of anticancer agents, as evidenced by several clinically relevant isatin-based compounds. In this study, 85 novel isatin derivatives were designed based on literature reports and evaluated using drug-likeness prediction, ADME profiling, molecular docking, and molecular dynamics simulations. The compounds were screened against VEGFR-2, EGFR, and caspase-6 to identify potential multi-target lead candidates. Based on their binding affinity and pharmacokinetic properties, 41 compounds were shortlisted for further evaluation. Among them, compound 4 exhibited the most favorable binding profile and stable interactions with the selected targets. These findings suggest that compound 4 represents a promising lead for further investigation. However, experimental studies, including enzyme inhibition, cell-based assays, and in vivo evaluation, are required to validate its therapeutic potential. Overall, this study highlights the usefulness of computational approaches in the discovery of novel isatin-based multi-target lead candidates for cancer therapy.
Findings identify compound 7e as a promising VEGFR-2-targeted anticancer lead with strong enzymatic inhibition, potent cytotoxicity, and a well-supported mechanistic profile integrating experimental and computational evidence.
A. Metwaly, Walid E. Elgammal, I. Eissa et al.· RSC Advances· 0 citations
NSCLC is still one of the leading causes of cancer mortality around the world, and there is a need for new therapeutic agents to overcome the limitations of existing targeted therapies, including the development of resistance to the drugs and significant side effects. In this study, several 1,2,3-triazole hybrids based on cabotegravir were assessed in an integrated computational methodology for their potential as anticancer agents by targeting a lung cancer-associated protein (PDB ID: 2ITY). Molecular docking was performed using PyRx 0.8 to assess binding affinities. The pharmaceutical properties of the compounds were evaluated for pharmacokinetic properties and the likelihood of toxicity, using SwissADME and pkCSM, respectively, and Gefitinib was used as the reference drug. Many of the compounds had statistically superior binding energies than Gefitinib (−7.5 kcal/mol); among the compounds studied, compounds 5e, 5h, and 6d showed the best binding energies [−10.2 kcal/mol].
The results revealed that the synthesised derivative 3h has potential binding affinity hence blocking the activity, and the synthesised piperazine derivatives are identified as promising lead compounds for further anticancer optimization.
Vaibhav Daund, Pooja Agarwal, A. Jain et al.· Asian Journal of Chemistry· 0 citations
C25, the pyrazolin derivative represents a novel multi-target ligand with potential applications as an anti-inflammatory, analgesic, and anti-neoplastic agent and highlights its promise as a lead scaffold for future drug development.
Mst Neha Islam Ema, A. Ashraful, K. Fatema et al.· Bangladesh Pharmaceutical Jo...· 0 citations
The development of selective vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors remains a promising strategy for anticancer therapy targeting tumor angiogenesis. In the study at hand, a novel benzanilide-based derivative, ACEB-Cl, was rationally designed by assimilating fundamental pharmacophoric characteristics essential for VEGFR-2 inhibition. ACEB-Cl was evaluated using a comprehensive approach that combined computational modeling, synthesis, and in vitro biological assessment. Density functional theory (DFT) calculations revealed a favorable electronic profile, with distinct nucleophilic and electrophilic regions that could support potential interactions within the VEGFR-2 binding pocket. Docking and molecular dynamics (MD) simulations suggested stable binding of ACEB-Cl within the ATP-binding pocket, supported by strong hydrophobic interactions and favorable binding free energy (ΔG = −63.21 kcal/mol). Following synthesis, ACEB-Cl confirmed potent anti-VEGFR-2 activity in an ELISA-based assay (IC50 = 0.086 0.002 M), showing higher potency than sorafenib. Western blot analysis further confirmed significant downregulation of phosphorylated VEGFR-2 in MDA-MB-231 cells. In vitro cytotoxicity studies revealed selective anticancer activity, with reduced toxicity toward normal Vero cells and favorable selectivity indices. Mechanistically, ACEB-Cl triggered G0/G1 phase arrest and significantly increased apoptotic cell death, highlighting its ability to suppress cancer cell proliferation. Additionally, ADMET and toxicity estimations indicated a balanced pharmacokinetic and safety profile, with improved solubility, acceptable absorption, and reduced toxicity risks compared to sorafenib. Overall, this integrated study pinpointed ACEB-Cl as a promising VEGFR-2targeted anticancer lead compound with strong inhibitory potency, and a clearly defined mechanism of action, supporting its progression for further improvement.
A. Metwaly, I. Eissa, Walid E. Elgammal et al.· Journal of Computational Bio...· 0 citations
