Small Molecule Docking of DNA Repair Proteins Associated with Cancer Survival Following PCNA Metagene Adjustment: A Potential Novel Class of Repair Inhibitors

Abstract

Natural and synthetic small molecules from the NCI Developmental Therapeutics Program (DTP) were employed in molecular dynamics-based docking with DNA repair proteins whose RNA-Seq based expression was associated with overall cancer survival (OS) after adjustment for the PCNA metagene. The compounds employed were required to elicit a sensitive response (vs. resistance) in more than half of the cell lines tested for each cancer. Methodological approaches included peptide sequence alignments and homology modeling for 3D protein structure determination, ligand preparation, docking, toxicity and ADME prediction. Docking was performed for unique lists of DNA repair proteins which predict OS for AML, cancers of the breast, lung, colon, and ovaries, GBM, melanoma, and renal papillary cancer. Results indicate hundreds of drug-like and lead-like ligands with best-pose binding energies less than −6 kcal/mol. Ligand solubility for the top 20 drug-like hits approached lower bounds, while lipophilicity was acceptable. Most ligands were also blood-brain barrier permeable with high intestinal absorption rates. While the majority of ligands lacked positive prediction for HERG channel blockage and Ames carcinogenicity, there was a considerable variation for predicted fathead minnow, honey bee, and Tetrahymena pyriformis toxicity. The computational results suggest the potential for new targets and mechanisms of repair inhibition and can be directly employed for in vitro and in vivo confirmatory laboratory experiments to identify new targets of therapy for cancer survival.

The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Is Synergistic With Radiotherapy in Models of Human Glioblastoma

“…In line with this, we and others have reported that inhibition of the DNA-dependent protein kinase catalytic subunit radio-sensitizes GBM and GSCs by inducing apoptotic cell death ( Timme et al, 2018 ; Fang et al, 2021 ). Many studies have also shown that natural compounds can inhibit DNA repair machinery when coupled with radiation, thereby acting as radio-sensitizing agents ( Peterson, 2019 ). In our study, we observed that PBI-05204 could attenuate DNA repair after RT as indicated by increased expression and permanence of γH2Ax over time and reduction of Rad51 and DNA-PKCs.…”

A New DNA Repair-Related Platform for Pharmaceutical Outlook in Cancer Therapies: Ultrashort Single-Stranded Polynucleotides

“…A comparison between the ligand amounts bound with (a) DNApolβ and (b) HSA show that the ligand-enzyme complex includes two molecules of ligand per one molecule of enzyme, while the ligand-HSA (control) pair contains just one ligand per HSA molecule (Figures 4,7,8). This is in favor to a mere fact of existence of two separate Mg 2+ -coordinating catalytic sites in β-and β-like DNA polymerases [8,10,[21][22][23]. Now, we evaluate the activation energy value for a ligand-enzyme complex dissociation following the data listed in Figure 4; Figure 8.…”

Covid-19 and Flavonoids: In silico Molecular Dynamics Docking to the Active Catalytic Site of SARS-CoV and SARS-CoV-2 Main Protease

“…The physical properties of flavonoids and prediction of their toxicology and Absorption, Distribution, Metabolism, Excretion (ADME) was performed using methods described previously (Peterson, 2019).…”