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Identification of indole-based natural compounds as inhibitors of PARP-1 against triple-negative breast cancer: a
Sridhar Priyankha1, Varatharaj Rajapandian2, Kandhan Palanisamy1
1Department of Chemistry, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, India.
Abstract:
Triple-negative breast cancer (TNBC) is the most aggressive kind of breast cancer known to mankind. It is a heterogeneous disease that is formed due to the missing estrogen, progesterone and human epidermal growth factor 2 receptors. Poly(ADP-ribose) polymerase-1 (PARP-1) protein helps in the development of TNBC by repairing the cancer cells, which proliferate and spread metastatically. To determine the potential PARP-1 inhibitors (PARPi), 0.2 million natural products from Universal Natural Product Database were screened using molecular docking and six hit compounds were selected based on their binding affinity towards PARP-1. The bio-availability and drug-like properties of these natural products were evaluated using ADMET analysis. Molecular dynamics simulations were conducted for these complexes for 200 ns to examine their structural stability and dynamic behaviour and further compared with the complex of talazoparib (TALA), an FDA-approved PARPi. Using MM/PBSA calculations, we conclude that the complexes HIT-3 and HIT-5 (-25.64 and -23.14 kcal/mol, respectively) show stronger binding energies with PARP-1 than TALA with PARP-1 (-10.74 kcal/mol). Strong interactions were observed between the compounds and hotspot residues, Asp770, Ala880, Tyr889, Tyr896, Ala898, Asp899 and Tyr907, of PARP-1 due to the existence of various types of non-covalent interactions between the compounds and PARP-1. This research offers critical information about PARPi, which could potentially be incorporated into the treatment of TNBC. Moreover, these findings were validated by comparing them with an FDA-approved PARPi.
Insights
Researchers screened natural products to find new treatments for triple-negative breast cancer (TNBC). Six compounds showed strong potential as Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors, offering new therapeutic options for aggressive TNBC.
Area of Science:
- Biochemistry
- Computational Chemistry
- Oncology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous cancer lacking estrogen, progesterone, and HER2 receptors.
- Poly(ADP-ribose) polymerase-1 (PARP-1) is crucial for TNBC cell repair, proliferation, and metastasis.
- Targeting PARP-1 with inhibitors (PARPi) is a promising therapeutic strategy for TNBC.
Purpose of the Study:
- To identify novel natural product-derived PARP-1 inhibitors (PARPi) for TNBC treatment.
- To evaluate the binding affinity, stability, and drug-like properties of potential PARPi candidates.
- To compare the efficacy of novel compounds with an FDA-approved PARPi, talazoparib.
Main Methods:
- Screening of 0.2 million natural products from the Universal Natural Product Database using molecular docking.
- Selection of six hit compounds based on binding affinity to PARP-1.
- ADMET analysis for bioavailability and drug-like properties.
- 200 ns molecular dynamics simulations and MM/PBSA calculations for binding energy assessment.
- Comparison with talazoparib (TALA) complex.
Main Results:
- Six natural product compounds exhibited significant binding affinity to PARP-1.
- HIT-3 and HIT-5 demonstrated superior binding energies (-25.64 and -23.14 kcal/mol) compared to talazoparib (-10.74 kcal/mol).
- Strong non-covalent interactions were observed between the top compounds and key PARP-1 hotspot residues (Asp770, Ala880, Tyr889, Tyr896, Ala898, Asp899, Tyr907).
- Molecular dynamics simulations confirmed the structural stability and dynamic behavior of the HIT-3 and HIT-5 complexes.
Conclusions:
- Novel natural product compounds HIT-3 and HIT-5 show potent inhibition of PARP-1.
- These compounds exhibit enhanced binding affinity and stability compared to the FDA-approved drug talazoparib.
- The identified compounds represent promising candidates for the development of new TNBC therapies.
