In silico study of the inhibition of DNA polymerase by a novel catalpol derivative

J Mol Model. 2011 Oct;17(10):2717-23. doi: 10.1007/s00894-010-0938-7. Epub 2011 Jan 13.

Abstract

In this work, a novel catalpol derivative (6,10,2',6'-tetraacetyl-O-catalpol), which was previously obtained by our group and shown experimentally to inhibit a type of Taq DNA polymerase, was studied in silico. Studies of the interaction of 6,10,2',6'-tetraacetyl-O-catalpol with the Klentaq fragment of the Taq DNA polymerase I from Thermus aquaticus helped to elucidate the mechanism of inhibition of the enzyme, and offered valuable information that can be used to propose substrate structural modifications aimed at increasing the binding affinity. Classical and semi-empirical methods were used to characterize the conformational preferences of this organic compound in solution. Using docking simulations, the most probable binding mode was found, and the stabilities of the docked solutions were tested in a series of molecular dynamics experiments. Results indicated that the mechanism of inhibition may be competitive, which agrees with previous binding experiments done with 6,10,2',6'-tetraacetyl-O-catalpol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Directed DNA Polymerase / chemistry*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Iridoid Glucosides / chemistry*
  • Iridoid Glucosides / pharmacology
  • Ligands
  • Molecular Dynamics Simulation*
  • Nucleic Acid Synthesis Inhibitors
  • Protein Binding
  • Protein Conformation
  • Solutions

Substances

  • Enzyme Inhibitors
  • Iridoid Glucosides
  • Ligands
  • Nucleic Acid Synthesis Inhibitors
  • Solutions
  • DNA-Directed DNA Polymerase