Selection of potential natural compounds for poly-ADP-ribose polymerase (PARP) inhibition in glioblastoma therapy by in silico screening methods

Glioblastoma (GBM), the most prevalent brain tumor, is one of the least treatable malignancies due to its propensity for intracranial spread, high proliferative potential, and innate resistance to radiation and chemotherapy. Current GBM therapy is limited due to unfavorable, non-specific therapeutic effects in healthy cells and the difficulty of small molecules to penetrate the blood brain barrier (BBB) and reach the tumor microenvironment. Adding PARP-1 inhibitors inhibit DNA repair enzymes thereby increasing the cytotoxicity of anticancer agents. Hence, we aimed to discover potential naturally occurring PARP-1 inhibitors that can be utilized in the treatment of glioma by using multiple in silico tools like molecular docking, absorption, distribution, metabolism, and excretion (ADME) profile, pharmacophore modeling, and molecular dynamic (MD) simulations. Among 43 phytocompounds we screened, two of them (Ellagic acid and Naringin) were discovered to be bound to the catalytic site of PARP-1 with an affinity more remarkable than commercially available PARP-1 inhibitors (Talazoparib, Niraparib, and Rucaparib) except Olaparib. The molecular interactions were analyzed, and data shows that bound entity attained a conserved domain via hydrogen bond interactions, polar interactions, and π-π stacking. Pharmacophore modeling studies showed electronic and steric features of ligands responsible for supramolecular interaction with PARP-1. ADME properties were studied, to assess drug-likeness, hydrophilic nature, hydrophobicity, brain permeability, and oral bioavailability of the natural PARP-1 inhibitors. The simulation study demonstrated the development of a stable complex between Naringin, Ellagic acid, and PARP-1 protein. Moreover, cell culture studies and animal investigations are essential to determine pharmacokinetics and pharmacodynamics.