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In-silico method for elucidation of prodigiosin as PARP-1 inhibitor a prime target of Triple-negative breast cancer
Priya Sundararajan1, Darjily Dharmaraj Rajaselvi1, Suseela Vivekananthan2
1Department of Microbiology, PSG College of Arts & Science, Coimbatore 641014, Tamil Nadu, India.
Abstract:
Triple-Negative Breast Cancer (TNBC) is found to be one of the life-threatening cancer. Poly (ADP-Ribose) Polymerase-1 (PARP-1) is overexpressed by those tumour cells, which become resistant to chemotherapies. Inhibition of PARP-1 has a considerable effect on treating TNBC. Prodigiosin is a valuable pharmaceutical compound that exhibits anticancer properties. The present study aims to virtually evaluate prodigiosin as a potent PARP-1 inhibitor using Molecular docking and Molecular Dynamics (MD) simulation studies. The PASS (Prediction of Activity Spectra for Substances) prediction tool evaluated the biological properties of prodigiosin. Then the drug-likeness and pharmacokinetic properties of prodigiosin were determined using Swiss-ADME software. It was suggested that prodigiosin obeyed Lipinski's rule of five and thus could act as a drug with good pharmacokinetic properties. Moreover, molecular docking was done with AutoDock 4.2 to identify the critical amino acids of the protein-ligand complex. It was indicated that prodigiosin has a docking score of -8.08 kcal/mol, which showed its effective interaction with crucial amino acid, His201A of PARP-1 protein. Further, MD simulation was performed using Gromacs software to validate the stability of the prodigiosin-PARP-1 complex. Prodigiosin was found to have good structural stability and affinity at the active site of PARP-1 protein. Additionally, PCA and MM-PBSA were calculated for the prodigiosin-PARP-1 complex, which revealed that prodigiosin has an excellent binding affinity towards PARP-1 protein. Prodigiosin can possibly be used as oral drug due to its PARP-1 inhibition through high binding affinity, structural stability, and receptor flexibility towards crucial amino acid residue His201A of PARP-1 protein. In-addition, in-vitro cytotoxicity, and apoptosis analysis of prodigiosin-treated TNBC cell line-MDA-MB-231 revealed that prodigiosin exhibited significant anticancer activity in 101.1 µg/mL concentration, when compared to commercially available synthetic drug cisplatin. Thus, prodigiosin could act as a potential candidate for treatment of TNBC than the commercially available synthetic drugs.
Insights
Prodigiosin shows potential as an oral drug for Triple-Negative Breast Cancer (TNBC) by inhibiting Poly (ADP-Ribose) Polymerase-1 (PARP-1). This natural compound exhibits strong binding affinity and anticancer activity, outperforming cisplatin in preliminary tests.
Area of Science:
- Computational chemistry and drug discovery
- Oncology and cancer therapeutics
- Pharmacology and medicinal chemistry
Background:
- Triple-Negative Breast Cancer (TNBC) is a life-threatening malignancy often associated with Poly (ADP-Ribose) Polymerase-1 (PARP-1) overexpression and chemotherapy resistance.
- Inhibition of PARP-1 is a promising therapeutic strategy for TNBC.
- Prodigiosin, a natural compound, possesses known anticancer properties.
Purpose of the Study:
- To virtually evaluate prodigiosin as a potential inhibitor of PARP-1 for TNBC treatment.
- To assess the drug-likeness, pharmacokinetic properties, and binding interactions of prodigiosin with PARP-1.
- To validate the efficacy of prodigiosin through in-vitro studies.
Main Methods:
- Prediction of Activity Spectra for Substances (PASS) for biological property evaluation.
- Swiss-ADME software for drug-likeness and pharmacokinetic assessments.
- Molecular docking (AutoDock 4.2) and Molecular Dynamics (MD) simulations (Gromacs) to analyze protein-ligand interactions.
- In-vitro cytotoxicity and apoptosis assays on MDA-MB-231 TNBC cell line.
Main Results:
- Prodigiosin demonstrated favorable drug-likeness, adhering to Lipinski's rule of five.
- Molecular docking revealed a strong binding affinity (-8.08 kcal/mol) with PARP-1, specifically interacting with His201A.
- MD simulations confirmed the stability and high binding affinity of the prodigiosin-PARP-1 complex.
- In-vitro studies showed significant anticancer activity of prodigiosin against MDA-MB-231 cells at 101.1 µg/mL, surpassing cisplatin.
Conclusions:
- Prodigiosin exhibits excellent binding affinity, structural stability, and pharmacokinetic properties, suggesting its potential as an oral drug for TNBC via PARP-1 inhibition.
- Prodigiosin demonstrates superior anticancer efficacy compared to cisplatin in preliminary in-vitro evaluations.
- Prodigiosin represents a promising therapeutic candidate for TNBC treatment.
