title: Targeting human DNA polymerase alpha for the inhibition of keratinocyte proliferation. Part 1. Homology model, active site architecture and ligand binding.
abstract: In order to understand the binding modes of human DNA polymerase alpha (pol alpha) inhibitors on a molecular level, a 3D homology model of the active site of the enzyme was proposed based on the application of molecular modelling methods and molecular dynamic simulations using available crystal coordinates of pol alpha relatives. Docking results for a series of known nucleotide analogue inhibitors were consistent with reported experimental binding data and offered the possibility to elucidate structure-activity relationships via investigations of active site-inhibitor interactions. Furthermore, the study could explain, at least partially, the inhibitory effect of aphidicolin on pol alpha. In molecular dynamics simulations, aphidicolin occupied the catalytic centre, but acted in a not truly competitive manner with respect to nucleotides. It destabilized the replicating "closed" form of the pol alpha and transferred the enzyme into the inactive "open" conformation. This result is consistent with recent experiments on the binding mode of aphidicolin.
authors.affiliation: Department of Pharmacology and Toxicology, Free University of Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Richartz
authors.forename: Monika
authors.initials: M
authors.lastname: Höltje
authors.forename: Birte
authors.initials: B
authors.lastname: Brandt
authors.forename: Monika
authors.initials: M
authors.lastname: Schäfer-Korting
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Höltje
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D016590:Aphidicolin / Q000494:pharmacology; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects*; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology*; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D063065:Organophosphonates / Q000494:pharmacology; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D016590:Aphidicolin; C053001:adefovir; D004256:DNA Polymerase I; D000225:Adenine