1 research outputs found
Ligand Binding Mode Prediction by Docking: Mdm2/Mdmx Inhibitors as a Case Study
The p53-binding domains of Mdm2 and
Mdmx, two negative regulators
of the tumor suppressor p53, are validated targets for cancer therapeutics,
but correct binding poses of some proven inhibitors, particularly
the nutlins, have been difficult to obtain with standard docking procedures.
Virtual screening pipelines typically draw from a database of compounds
represented with 1D or 2D structural information from which one or
more 3D conformations must be generated. These conformations are then
passed to a docking algorithm that searches for optimal binding poses
on the target protein. This work tests alternative pipelines using
several commonly used conformation generation programs (LigPrep, ConfGen,
MacroModel, and Corina/Rotate) and docking programs (GOLD, Glide,
MOE-dock, and AutoDock Vina) for their ability to reproduce known
poses for a series of Mdmx and/or Mdm2 inhibitors, including several
nutlins. Most combinations of these programs using default settings
fail to find correct poses for the nutlins but succeed for all other
compounds. Docking success for the nutlin class requires either computationally
intensive conformational exploration or an “anchoring”
procedure that incorporates knowledge of the orientation of the central
imidazoline ring