Structural Approach To Identify a Lead Scaffold That Targets the Translesion Synthesis Polymerase Rev1
| Autor: | Socheata Lim, Dmitry M. Korzhnev, Zuleyha Ozen, Alessandro A. Rizzo, M. Kyle Hadden, Radha Charan Dash |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Scaffold Phenazopyridine DNA Repair Multiple forms General Chemical Engineering Antineoplastic Agents Library and Information Sciences Biology Molecular Dynamics Simulation Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Neoplasms Drug Discovery Humans Protein Interaction Maps Polymerase Structural approach Mechanism (biology) Nuclear Proteins General Chemistry Nucleotidyltransferases Computer Science Applications Cell biology Molecular Docking Simulation 030104 developmental biology chemistry 030220 oncology & carcinogenesis biology.protein REV1 Thermodynamics DNA Human cancer DNA Damage |
| Zdroj: | Journal of chemical information and modeling. 58(11) |
| ISSN: | 1549-960X |
| Popis: | Translesion synthesis (TLS) is a mechanism of replication past damaged DNA through which multiple forms of human cancer survive and acquire resistance to first-line genotoxic chemotherapies. As such, TLS is emerging as a promising target for the development of a new class of anticancer agents. The C-terminal domain of the DNA polymerase Rev1 (Rev1-CT) mediates assembly of the functional TLS complex through protein-protein interactions (PPIs) with Rev1 interacting regions (RIRs) of several other TLS DNA polymerases. Utilizing structural knowledge of the Rev1-CT/RIR interface, we have identified the phenazopyridine scaffold as an inhibitor of this essential TLS PPI. We demonstrate direct binding of this scaffold to Rev1-CT, and the synthesis and evaluation of a small series of analogues have provided important structure-activity relationships for further development of this scaffold. Furthermore, we utilized the umbrella sampling method to predict the free energy of binding to Rev1-CT for each of our analogues. Binding energies calculated through umbrella sampling correlated well with experimentally determined IC |
| Databáze: | OpenAIRE |
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