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A Novel Pyridopyrimidine Derivative as a Potential Breast Cancer Agent: DFT, Docking, MD Simulation, and Cytotoxic
Anushree Maurya1, Lamya H Al-Wahaibi2, Mamta Pal1
1Department of Physics, University of Lucknow, Lucknow, India.
Abstract:
Breast cancer is a pervasive and deadly disease, affecting women worldwide. Chemotherapy for breast cancer primarily targets receptors, such as ERα, PR, CDK2, and EGFR, whose overexpression contributes to the initiation and progression of cancer. In this study, a tetrahydropyrido[4,3-d]pyrimidine derivative 4-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine was used as an inhibitor of these receptors. It employs density functional theory calculations and experimental investigations of the compound. Molecular docking studies were conducted to evaluate the potential of the compound as an inhibitor of CDK2 (2J9M), PR (4OAR), EGFR (1M17 & 2J6M), ERα (3ERT), and resulting binding affinities were -7.2, -6.9, -6.6, -6.2, and -6.9 kcal/mol, respectively. Molecular dynamics simulations performed on docked complex with highest binding affinity further confirm its dynamic stability inside the binding cavity. The cytotoxic performance against the MCF-7 and MDA-MB-231 breast cancer cell lines was examined using MTT assay, and obtained IC50 values were 62.5 and 500 µg/mL, respectively. Dual AO/PI staining was used to evaluate the ability of the compound to induce apoptosis in MCF-7 cells. Furthermore, the compound met various pharmacokinetic criteria, suggesting its drug-like properties. Considering the effectiveness of pyrimidine-piperazine derivatives in cancer treatment, this compound holds promise as a lead compound for novel breast cancer therapies.
Insights
A novel pyrimidine-piperazine derivative shows promise as a breast cancer treatment by inhibiting key receptors like estrogen receptor alpha (ERα) and epidermal growth factor receptor (EGFR). This compound effectively reduced cancer cell viability and induced apoptosis, indicating potential for new therapies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Computational Chemistry
Background:
- Breast cancer is a significant global health challenge, often driven by overexpressed receptors like ERα, PR, CDK2, and EGFR.
- Current chemotherapy often targets these specific receptors for treatment.
Purpose of the Study:
- To investigate a novel tetrahydropyrido[4,3-d]pyrimidine derivative as a potential inhibitor of key breast cancer receptors.
- To evaluate its efficacy and drug-like properties for novel breast cancer therapies.
Main Methods:
- Density functional theory (DFT) calculations and experimental investigations.
- Molecular docking and molecular dynamics simulations to assess binding affinities and stability.
- MTT assay and AO/PI staining to evaluate cytotoxicity and apoptosis induction in breast cancer cell lines (MCF-7, MDA-MB-231).
Main Results:
- The compound exhibited strong binding affinities for CDK2, PR, EGFR, and ERα, with molecular docking scores ranging from -6.2 to -7.2 kcal/mol.
- Significant cytotoxic effects were observed against MCF-7 cells (IC50 = 62.5 µg/mL) and MDA-MB-231 cells (IC50 = 500 µg/mL).
- The compound demonstrated the ability to induce apoptosis in MCF-7 cells and satisfied pharmacokinetic criteria.
Conclusions:
- The studied tetrahydropyrido[4,3-d]pyrimidine derivative shows significant potential as a lead compound for developing new breast cancer treatments.
- Its ability to inhibit multiple key receptors and induce apoptosis warrants further investigation for therapeutic applications.
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