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Molecules 2019, 24(3), 645; https://doi.org/10.3390/molecules24030645

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

1
Department of Healthcare Policy and Research, Weill Cornell Medical College, Cornell University, New York City, NY 10065, USA
2
Center for Biostatistics, Institute for Academic Medicine, Houston Methodist Research Institute, 6565 Fannin Street, Houston, TX 77030, USA
Received: 5 January 2019 / Revised: 5 February 2019 / Accepted: 11 February 2019 / Published: 12 February 2019
(This article belongs to the Section Medicinal Chemistry)
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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. View Full-Text
Keywords: small molecule; ligand; receptor; docking; molecular dynamics; DNA repair; inhibition; PCNA; ADME; toxicology small molecule; ligand; receptor; docking; molecular dynamics; DNA repair; inhibition; PCNA; ADME; toxicology
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Peterson, L.E. Small Molecule Docking of DNA Repair Proteins Associated with Cancer Survival Following PCNA Metagene Adjustment: A Potential Novel Class of Repair Inhibitors. Molecules 2019, 24, 645.

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