Computational Exploration of Fluorocyclopentenyl-purines and-pyrimidines Derivatives as Potential Inhibitors of Epidermal Growth Factor Receptor (EGFR) for the Treatment of Breast Cancer.

The Epidermal Growth Factor Receptor (EGFR) is an important therapeutic target for the treatment of a variety of epithelial malignancies, including breast cancer, in which EGFR is aberrantly expressed.The fluorocyclopentenyl-purine-pyrimidines derivatives, which have previously been described as powerful compounds against breast cancer, were selected to investigate their potential against EGFR using computational tools in an effort to obtain potent inhibitors with fewer adverse effects. The molecule's chemical reactivity and stability were assessed by determining the HOMO-LUMO energy gap using density functional theory (DFT) calculations. Among all the selected compounds, PU4 displayed a HOMO-LUMO gap of 0.191 eV. Additionally, molecular docking analysis was performed to assess the binding affinities of PU4 within the active pocket of EGFR-TK. The compound PU4 showed potent interactions with EGFR exhibiting -32.3 kJ/mol binding energy which was found best as compared to gefitinib i. e., -27.4 kJ/mol which was further validated by molecular dynamics simulations and ADMET analysis. The results of these analyses indicate that the top hits obtained from the virtual screening possess the ability to act as effective EGFR inhibitor. Therefore, it is recommended to further investigate the inhibitory potential of these identified compounds using in vitro and in vivo approaches.

Hybrids of thiazolidinone with 1,2,3-triazole derivatives: design, synthesis, biological evaluation, in silico studies, molecular docking, molecular dynamics simulations, and ADMET profiling.

A new series of thiazolidinone linked 1,2,3-triazole hybrids 5a-h was designed and synthesized using the copper-catalyzed Huisgen azide-alkyne cycloaddition (CuAAC) between thiazolidinone linked alkyne and aromatic azides. The structures of the newly synthesized compounds were established by NMR (1H and 13C) and HRMS. The targeted thiazolidinone-1,2,3-triazole hybrids were evaluated for their cytotoxic activity against four human cancer cell lines, including fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast carcinoma (MCF-7 and MDA-MB-231) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliun bromide (MTT). The obtained data showed that most of these compounds have moderate anti-proliferative activity with IC50 values between 10.26 ± 0.71 and 53.93 ± 1.20 µM. The compound 5a exhibited higher activity with an IC50 value of 10.26 ± 0.71 µM, compared to 5d with an IC50 value of 11.56 ± 1.98 µM for the HT-1080 and MCF-7 cancer cells line, respectively. Moreover, Annexin-V apoptosis was assessed by flow cytometry for hybrid compounds 5a and 5d against HT-1080 and MCF-7 competitor cell lines, as they increase the level of active caspase 3/7. The experimental results were further confirmed by docking studies followed by molecular dynamic simulations. Both the potent derivatives i.e. 5a and 5d have comparable docking scores and MD simulations results showed that the docked complex of 5a is somewhat more stable than 5d primarily for protein p53. The ADMET profile of both derivatives established their safety zone and drug-like potential.Communicated by Ramaswamy H. Sarma.