Drug design module (DRUG)

Introduction.

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.

Reading/writing drugs from/into drug coordinate files

Reading cambridge database files (GETCSD)

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.

Reading TRIPOS MOL2 files (GETML2)

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.

creating a small molecule topology entry (DRGTOP)

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.

Drug docking options

Dock with WHAT IF's shitty docker (WIDOCK)

In a moment of total overconfidence I wrote a docking option in WHAT IF. I can only encourage you to look at the other programs listed here.

Dock with WHAT IF's shitty docker (DCKOPT)

In a moment of total overconfidence I wrote a docking option in WHAT IF. I can only encourage you to look at the other programs listed here.

Dock with WHAT IF's manual docker (MANDCK)

In a moment of total overconfidence I wrote a manual docking option in WHAT IF. I can only encourage you to look at the other programs listed here.

docking a drug (LIGIN)

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.

Docking flexible drugs with (FLEXX)

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.

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).

Prepare files for FLEXX (INIFLX)

FLEXX requires several input files. This option helps you to prepare those. At present the protein-surface file and the cavity-in-which-to-dock file are being generated. The MOL2 file is expected to be added soon. This option assumes that you have read the receptor with GETMOL, and that you have put the molecule on the screen with SHOALL in the GRAFIC menu. Although not obligatory, it seems wise to have only the receptor protein(s) (and perhaps some waters and ligands) in the soup, and no other proteins or nucleic acids.

You will be prompted for the residue range of the receptor. In principle you should either know exactly what you are doing, or enter the full receptor as input range. After that some CPU time is spent on the calculation of a cavity/cave map (see the CAVITY option in the MAP menu). This can take up to a few minutes. This cavity map will be put at the screen. (You will be prompted for MOL-items and MOL-objects, just hit return every time).

After a while the GO command will be executed automatically. You see all cavities/caves represented by chicken wires. If you rotate the picture a little bit you see that all cavities/caves are filled with crosses. The text box on the top right of the screen asks you to pick a cavitie. To do so you should pick a cross in the cavity you want to use for the docking study. Normally this is the largest cavity. After you picked the first cavity the text at the top right of the screen changes into 'pick cavity/CHAT' indicating that WHAT IF accepted your cavity choice. You can now pick a second cavity, but according to me you should only do that if you observe two cavities near each other that should actually have been one large cavity. After clicking CHAT you get one more MOL-item: The contours of the cavity/cave that you selected.

The SETACC command in the ACCESS menu will be executed automatically on the range that you selected upon starting this option. So, you will only be prompted for the environment part of the ACCESS option. WHAT IF will now automatically generate two PDB files:

POCKET.PDB contains all atoms that are near the selected cavity/cave.

SURFACE.PDB contains all atoms that are at the receptor surface.

Prepare files for FLEXX (ANIFLX)

The option INIFLX (see above) prepares files for FLEXX using user interaction. The command ANIFLX will do the same as INIFLX, but it will not use the graphics device and it will use defaults everywhere, thereby making user interaction not needed.

Interaction with the RELIWE drug docking database

These options are not useful for anybody outside the RELIWE project.

DOCKDB Substructure search via smiles-code (SUBSTR)

Substructure search via smiles-code

DOCKDB Substructure search via fragment name (SUBFRA)

Substructure search via fragment name

DOCKDB Find pairs of contacting residues (FNDCAA)

Find pairs of contacting residues

DOCKDB Find (and display) a PDB file (FNDPDB)

Find (and display) a PDB file

DOCKDB List of searchable PDB files (LSTDDB)

List of searchable PDB files

DOCKDB Initialize for DOCKDB usage of FLEXX (GETFLX)

Initialize for DOCKDB usage of FLEXX

DOCKDB Load file from database (GETDDB)

Load file from database

DOCKDB Demonstration command (FNDCPX)

Demonstration command

DOCKDB interactive VQL query (DDBVQL)

interactive VQL query

DOCKDB gets started (do first, but only once) (INIDDB)

gets started (do first, but only once)