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Updated: Jun 4, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Rational design, synthesis, biological evaluation, molecular docking, and molecular dynamics of substituted uracil
Ebtessam A Basiony1, Allam A Hassan2, Mohamed Elsawalhy3
1Department of Chemistry, Faculty of Science, Menoufia University, Egypt; Department of Photochemistry (Synthetic Unit), Chemical Industries Research Institute, National Research Centre, Cairo 12622, Egypt.
Abstract:
An efficient synthesis of a series of uracil analogous was performed to obtain new potential anticancer agents. The cytotoxic effect of the synthesized derivatives was assessed in vitro against three cancer cell lines, namely hepatic cancer (HepG-2), colon cancer (HCT-116), and breast cancer (MCF-7). Among the tested compounds, 5, 11 and 15 stood as potent uracil derivatives with pan cytotoxicity against the 3 cell lines out-performing the reference compound 5-FU. Furthermore, selected compounds underwent thymidylate synthase (TS) enzyme inhibition assay and demonstrated effective inhibition of the enzyme's catalytic activity. Thereafter, flow cytometric apoptosis and protein expression of pro- and anti-apoptotic markers Bax, BCL-2, PI3K, and STAT1 proteins assays were performed employing the most active compound on the respective most responsive cell line and compounds demonstrated effectiveness in inducing apoptosis in the treated cell lines. Finally, in silico studies encompassing molecular docking and molecular dynamics studies were also conducted to predict the interaction mechanisms and stability of the active compounds within the active site of their biological target TS.
Insights
New uracil derivatives show potent anticancer activity against liver, colon, and breast cancer cells. These compounds effectively inhibit thymidylate synthase (TS) and induce apoptosis, offering promising therapeutic potential.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Uracil analogs are crucial in cancer chemotherapy.
- Developing novel anticancer agents with improved efficacy and reduced toxicity is a priority.
- Targeting thymidylate synthase (TS) is a validated strategy for cancer treatment.
Purpose of the Study:
- To synthesize novel uracil derivatives as potential anticancer agents.
- To evaluate the in vitro cytotoxic effects of these derivatives against various cancer cell lines.
- To investigate the mechanism of action, including TS inhibition and apoptosis induction.
Main Methods:
- Chemical synthesis of uracil analogs.
- In vitro cytotoxicity assays using HepG-2, HCT-116, and MCF-7 cell lines.
- Thymidylate synthase (TS) enzyme inhibition assays.
- Flow cytometry for apoptosis analysis and Western blotting for apoptotic markers (Bax, BCL-2, PI3K, STAT1).
- In silico molecular docking and molecular dynamics simulations.
Main Results:
- Several synthesized uracil derivatives exhibited significant pan-cytotoxicity against tested cancer cell lines, outperforming 5-fluorouracil (5-FU).
- Compounds 5, 11, and 15 demonstrated potent cytotoxic effects.
- The active compounds effectively inhibited thymidylate synthase (TS) activity.
- Apoptosis induction was confirmed through flow cytometry and modulation of key apoptotic proteins.
- In silico studies predicted stable interactions of active compounds within the TS active site.
Conclusions:
- The synthesized uracil derivatives represent promising candidates for novel anticancer drug development.
- These compounds exert their anticancer effects through TS inhibition and induction of apoptosis.
- Further investigation and optimization are warranted to translate these findings into clinical applications.
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