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.
Keywords: Triple-negative breast cancer; binding free energy; molecular dynamics simulations; poly(ADP-ribose) polymerase; protein-ligand complexes.