In-silico method for elucidation of prodigiosin as PARP-1 inhibitor a prime target of Triple-negative breast cancer

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.

Keywords: Breast cancer; MD simulation; Molecular docking; PARP-1; Pharmacokinetics; TNBC.