LIDAEUS

 
 

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Lidaeus: LIgand Discovery At Edinburgh UniverSity


LIDAEUS (LIgand Discovery At Edinburgh UniverSity) is a high throughput in-silicon screening program written by Dr Paul Taylor of the Institute of Structural and Molecular Biology, University of Edinburgh. LIDAEUS is a highly adaptable and modular rigid body docking in-silicon screening code written in C++. The following example of a in-silicon screening run uses the pdb file 1FKJ representing the protein FKBP12.


The first stage of a run is to obtain (normally from the protein databank) a pdb file of the protein in complex with its natural ligand. The natural ligand is then removed from the file and a mol2 file generated representing the ligand. A map file generation program is then used to generate three maps. The code to do this is an adaptation of methods originally implemented by Professor Malcolm Walkinshaw.

 


Figure 1. Solvent accessible surface area of FKBP12 (pdbid: 1fkj)

 

Using the maps and the natural ligand to define the binding pocket, the map generation program defines a set of site points. At this stage, all of the information required to carry out the run has been generated.

 


Figure 2. Site points generated and overlaid onto protein surface.

 

A LIDAEUS pipeline is comprised of the following.

 


 

  1. 1.Preen reads input in the sdf file format. For any use to be made of the molecule, the atoms must be "typed", this process adds more information such as hybridisation states to the atom. Typing is done using an extensive set of rules and is aided by recursive ring finding routines that traverse the molecules connection table to a depth of eight atoms looking for ring structures.


  1. 2.After information has been added to the molecule by preen, pose tries to fit the molecule to the set of site points in as many ways as possible. Shown as below is Pose matching a molecule to a set of site points.


  1. 3.

     
  2. 4.This process gives the score a ligand would achieve if positioned over the suggested site points in the binding pocket of a protein. At this stage the score module can apply energy minimisation techniques to the ligands position to achieve a better score.


  1. 5.Sort is simple in its operation, with parameters read in from a configuration file requesting (for example) that the top 1000 ligands be kept; score simply reads in the scored sdf entries, maintaining a list of the best 1000 top scoring ligands. The figure below represents high scoring ligand docked to FKBP12.


  1. 6.

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contacts:


Facilities Manager:

Dr. Martin Wear

Rm. Swann 3.20

Tel (+44) 0131 6507054

Fax (+44) 0131 6507055

email: martin.wear@ed.ac.uk


In Silico screening/database mining:

Dr. Paul Taylor

Rm. PWB 113

Tel (+44) 0131 6507058

Fax (+44) 0131 6507055

email: prt@staffmail.ed.ac.uk


Protein Technologist:

Dr. Matt Nowicki

Rm. Swann 3.19

Tel (+44) 0131 6507054

Fax (+44) 0131 6507055

email: matthew.nowicki@ed.ac.uk


Facilities:


CTCB-Home

Protein Production

Biophysical Characterisation

In Silico Screening

Training


Links:


On-line Booking

Core Column Library


Access Charges/Costs:


Access Charges/Costs

 

Location:

The University of Edinburgh,

Level 3 Michael Swann Building,

King’s Buildings,

Mayfield Rd.,

EH9 3JR,

UK


Lab 3.10

In Silico Tools for Screening for Drug Leads