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Small molecule docking of DNA repair proteins associated with cancer survival following PCNA metagene adjustment: A potential novel class of repair inhibitors

Leif E. Peterson
doi: https://doi.org/10.1101/485375
Leif E. Peterson
1Department of Healthcare Policy and Research, Weill Cornell Medical College, Cornell University, New York City, New York 10065 USA
2Center for Biostatistics, Institute for Academic Medicine, Houston Methodist Research Institute, 6565 Fannin Street, Houston, Texas 77030 USA
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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 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.

  • ABBREVIATIONS

    ADME
    Absorption, distribution, metabolism, and excretion
    AML
    Acute myelogenous leukemia
    BBB
    Blood brain barrier
    BE
    Binding energy (kcal/mol)
    CNS
    Central nervous system
    CYP
    Cytochrome P-450 enzymes
    GBS
    Glioblastoma multiforme
    HERG
    Human ether-a-go-go related gene
    HBA
    Hydrogen bond acceptors
    HBD
    Hydrogen bond donors
    HIA
    Human intestinal absorption
    LogS
    Solubility
    LogP
    Lipophilicity
    MW
    Molecular weight (Daltons)
    MD
    Molecular dynamics
    PCNA
    Proliferating cell nuclear antigen
    RotB
    Number of rotatable bonds (covalent)
    TCGA
    The Cancer Genome Atlas
    TPSA
    Topological surface area
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted December 03, 2018.
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    Small molecule docking of DNA repair proteins associated with cancer survival following PCNA metagene adjustment: A potential novel class of repair inhibitors
    Leif E. Peterson
    bioRxiv 485375; doi: https://doi.org/10.1101/485375
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    Small molecule docking of DNA repair proteins associated with cancer survival following PCNA metagene adjustment: A potential novel class of repair inhibitors
    Leif E. Peterson
    bioRxiv 485375; doi: https://doi.org/10.1101/485375

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