WHAT IF is not a real drug design and discovery system, but it has
several options that can be of use in a drug design environment.
These options can be separated in administrative options,
small molecule specific options, docking related options, and miscelania.
If you use the SRFMAP option in the MAP menu, and cleverly combine this
with options in the MASMAP menu, it is possible to create a negative
density image of the protein(s) in the soup. If you now place a small
molecule roughly in this density, you can use the DENFIT option to
optimize the convolution of the density and the atoms in the small
molecule.
This option does the same as the DENFIT option (see above), but
additionally bumps between the small molecule and the protein(s)
are penalized.
The command GETCSD will cause WHAT IF to prompt you for the name
of the CSD coordinate file. It will read the coordinates from this
file, and it will automatically convert them from fractional to
orthogonal coordinates.
If the name of the drug that is read from the CSD file is not
acceptable to WHAT IF, you are prompted for the residue name.
The command GETCSD will cause WHAT IF to prompt you for the name
of the Tripos MOL2 coordinate file. It will read the coordinates
from this file and add them to the SOUP.
The command DRGTOP activates Daan van Aalten's small molecule
drug topology generating program. You can put the output topology
file, and put it in the WHAT IF topology file. WHAT IF can do a few
more things with drugs for which pre-calculated topology
entries exist than with drugs for which the topology has to
be generated upon reading the molecule.
WHAT IF provides several mechanisms for docking drugs. The command
LIGIN activates Vladimir Sobolev's LIGIN program. You will be
prompted for the small molecule and for the range of residues
that forms the molecule(s) in which you want to dock the drug.
If you have the proigram FlexX available on your machine, you can use
it from within WHAT IF with the command FLEXX in the DRUG menu.
This will activate the FlexX program. You are refered to the FlexX
manual for further details. The following is a short description
of FlexX to wet your appetite...
FlexX is a computer program for predicting receptor-ligand interactions.
For a given receptor and a ligand, FlexX predicts the geometry of the
complex as well as the free energy of binding. In this first version of
FlexX, the receptor is assumed to be rigid. Thus, the receptor must be
given in a conformation, which is similar to the bound state. Manual
intervention should be as small as possible during the docking process. The
only part, which is not automated yet and must be done manually, is the
definition of a base fragment in the ligand. Summarized, FlexX can be
useful in the following situation:
You have a good three dimensional model of the receptor and you know
thelocation of the active site. You have a set of ligands and you want
to know, wether and how each of them binds to your receptor model.
Before you start working with FlexX, we want to mention that FlexX is
a quickly developed prototype software. We have tested the program with a
continuously growing set of receptors and ligands, but we are sure that
FlexX is far away from being 'free of errors'.
FlexX is developed by the Lengauer group in Bonn,
in the framework of the project RELIWE.
RELIWE is a German abbreviation for 'Prediction of receptor-ligand
interactions'. The project is funded by the German Federal Ministry for
Education, Science, Research and Technology (BMBF)} at the German National
Research Center for Computer Science (GMD), Institute for Algorithms and
Scientific Computing (SCAI).