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Drug repurposing for the identification of new Bcl-2 inhibitors: In vitro, STD-NMR, molecular docking, and dynamic
Noor Rahman1, Humaira Zafar2, Atia-Tul-Wahab2
1H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Background:
The anti-apoptotic protein B-Cell Lymphoma 2 (Bcl-2) is a key target for the development of anti-cancer agents, as its overexpression can render cancer cells resistant to chemotherapeutic treatments.
Aims And Objectives:
The current study has systematically evaluated a library of FDA-approved drugs for Bcl-2 inhibition using a drug repurposing strategy via in vitro, biophysical, and in-silico techniques.
Materials And Methods:
In vitro anticancer activity was performed, followed by apoptosis assay. The selected compounds were subjected to Saturation Transfer Difference Nuclear Magnetic Resonance (STD-NMR) spectroscopy, molecular docking, and molecular dynamic simulation for ligand-protein interactions.
Key Findings:
In the initial screening, seventy-five (75) drugs were evaluated against the HL-60 (human blood promyelocytic leukemia) cancer cell line. Among them, paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate showed significant anti-proliferative activity (IC50 = 9.733 ± 0.524, 11.940 ± 0.079, 12.376 ± 1.242, and 6.155 ± 0.363 μM, respectively), in comparison to the reference drug venetoclax (IC50 = 7.086 ± 0.041 μM). This indicated that the test drugs have comparable IC50 values to the standard drug. Furthermore, the drugs were able to induce apoptosis in HL-60 cells. These drugs showed interactions with Bcl-2 protein in STD-NMR analysis. Docking and MD simulation studies further supported the interaction of these drugs with Bcl-2 protein, mainly via hydrophobic contacts leading to stable drug-Bcl-2 complexes.
Significance:
This study, identifies paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate as significant Bcl-2 inhibitors and needs further pre-clinical and clinical studies for potential anti-cancer agents' evaluation.
Insights
This study repurposed FDA-approved drugs to find novel Bcl-2 inhibitors for cancer therapy. Paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate demonstrated significant anti-proliferative activity and Bcl-2 protein interaction.
Area of Science:
- Oncology
- Pharmacology
- Biophysics
Background:
- Overexpression of the anti-apoptotic protein B-Cell Lymphoma 2 (Bcl-2) contributes to cancer cell resistance to chemotherapy.
- Targeting Bcl-2 is a key strategy for developing novel anti-cancer agents.
Purpose of the Study:
- To systematically screen FDA-approved drugs for Bcl-2 inhibition using a drug repurposing approach.
- To evaluate the in vitro anticancer activity and apoptosis-inducing potential of identified compounds.
- To elucidate the ligand-protein interactions between candidate drugs and Bcl-2 using biophysical and in-silico methods.
Main Methods:
- In vitro anticancer activity assays and apoptosis assays were performed on the HL-60 cancer cell line.
- Selected compounds underwent Saturation Transfer Difference Nuclear Magnetic Resonance (STD-NMR) spectroscopy.
- Molecular docking and molecular dynamic simulations were employed to analyze drug-Bcl-2 interactions.
Main Results:
- Seventy-five FDA-approved drugs were screened; paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate exhibited significant anti-proliferative activity against HL-60 cells.
- These drugs demonstrated comparable IC50 values to the reference drug venetoclax and induced apoptosis in cancer cells.
- STD-NMR, docking, and molecular dynamic simulations confirmed interactions between these drugs and the Bcl-2 protein, primarily through hydrophobic contacts.
Conclusions:
- Paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate are identified as potent Bcl-2 inhibitors.
- These repurposed drugs warrant further pre-clinical and clinical investigation as potential anti-cancer agents.
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