Evaluation of pyrrole-2,3-dicarboxylate derivatives: Synthesis, DFT analysis, molecular docking, virtual screening and in vitro anti-hepatic cancer study

Abstract

Abstract Novel anti-hepatic carcinoma drugs are of great therapeutic significance in the treatment of different types of hepatic cancers. Since last decade, there has been a progressive improvement in computational drug designing strategies. Human topoisomerase-II (Topo-II) and human platelet derived growth factor receptor-α (PDGFR-α) have been identified as main enzymes involved in hepatic carcinoma. In the current work, we assessed novel pyrrole-2,3-dicarboxylate derivatives as potential anti-cancer agents using docking, virtual screening and experimental analyses. Pyrrole-2,3-dicarboxylate derivatives which we have evaluated in this study were synthesized and characterized by UV, IR, ESI-MS, 1H and 13C NMR spectroscopic techniques. Structural validation was done using quantum chemical calculations using Density Function Theory (DFT) employing B3LYP method and 6-311++G(d,p) basis set. Potential energy distribution (PED) for normal vibrational modes was computed by VEDA4. The HOMO and LUMO analysis was carried out to determine the charge transfer within the molecule. The synthesized compounds were tested in-silico and in-vitro for anti-cancer activity; Docking studies were performed against topo-II and PDGFR-α. By utilizing ligand based pharmacophore generation approach and virtual screening against control drugs (Doxorubicin Hydrochloride and Rituximab) fifty-one novel molecules have been proposed that displayed highest binding affinities, least binding energies and effective druglikeness. The docking analyses revealed that Met782, Val785, Asn786, Gly813, Lys814 and Ile43 were important interacting residues for topo-II and Glu556, Ile557, Arg558, Arg560, Glu789 and Arg817 for PDGFR-α receptor-ligand interaction. Absorption, distribution, metabolism, excretion and toxicological (ADMET) calculations predicted drugs to have improved pharmacokinetic properties. The compounds may be proven to be novel therapeutic candidates to cure cancer. The anti-hepatic carcinoma activity of compounds 1and 29 was evaluated against human liver carcinoma HepG2 cells using MTT assay, nuclear fragmentation and ROS generation analysis. The result of MTT assay revealed that these synthesized compounds significantly inhibited the growth of HepG2 cells in a dose-dependent manner. In addition to this, increment in condensed apoptotic nuclei and augmentation of intracellular reactive oxygen species (ROS) at higher doses of tested compounds showed apoptotic cell death of HepG2 cells. In brief, the cytotoxicity data revealed that compounds 1 and 29 possessed potent anti-hepatic carcinoma activities against HepG2 cells.