Designing Potent Inhibitors for Survivin Protein

Abstract

Malignant neoplasm is associated with inappropriate activation of the apoptosis. Apoptosis plays crucial roles in cell cycle regulation and tissue development; however, this process is believed to be aberrant, when the inhibitor of apoptosis proteins (IAPs), particularly, survivin is directly interfering with caspases during the apoptosis mechanism. Survivin is known to be highly expressed in human malignancies and also responsible for tumor resistance. Though a wide variety of antineoplastic compounds is available to hinder survivin gene promoter activity, recent evidences report their undesired therapeutic response towards several carcinomas. Developing some probable survivin inhibitors is therefore required to assure a better therapeutic profile to combat cancer. In this study, we have collected 46 potent compounds from the BindingDB and ZINC15 database which were later followed by the structural optimization using the Semi-empirical method. These compounds were docked against the binding site of survivin protein and three top-ranked compounds were then selected from the results with better predicted binding energies that may act as potential inhibitors. The top-ranked compounds BDBM50209196, ZINC28821535, BDBM50209201 have shown the predicted binding energies of -9.6, -8.9 and -8.87 kcal/mole, respectively, forming binding interactions with the amino acid residues of the binding site. Molecular dynamics simulation was then employed for BDBM50209196, ZINC28821535, BDBM50209201, YM155 complexes with survivin and the apo protein to investigate the binding stability and structural variation in physiological condition. To understand drug properties, the quantum mechanical calculation was employed to optimize the potential compounds using M062x/6-31G(d) level of theory and all compounds show thermodynamic stability. Charge distribution, dipole moment and thermodynamic properties such as electronic energy, enthalpy and Gibbs free energy of these optimized compounds are also explored to evaluate the drug property. Moreover, these three compounds indicated good pharmacokinetic properties. The study would be a key resource as a future guideline to design new cancerous protein inhibitors for cancer therapy.

Keywords: Survivin, Virtual screening, Molecular dynamics simulation, DFT, ADMET