Ligand-Protein Docking

Computer Aided Drug Design Practical for

3rd Year Pharmacy Students

SYBYL 7.0 Basics

Mouse button Function
left  selection
mid + right scale
right X-Y rotation
left + right Z rotation
mid X-Y translation

 

Working with Molecules

 

Protein

  1. Load a protein (HIV-1 protease).
  2. Name the protein.
  3. Add hydrogens to the protein.
  4. Compute charges for this protein.
  5. Save the protein
  6. Zoom out to view the entire protein.
  7. Find secondary structures in protein.
  8. Construct a three-dimensional shaded ribbon for the protein.
  9. Highlight catalytic triad ASP25, THR26 and GLY27 by spacefill representation.
  10. Question 1: Where is the active site of the protein?
  11. Delete the protein.

 

Ligand

  1. Load a drug (A77800).
  2. Name the ligand.
  3. Add hydrogens to this drug.
  4. Compute charges for this drug.
  5. Conduct molecular mechanics computation to find lowest potential energy conformation for this drug.
  6. Save the drug
  7. Create molecular surface of this drug.
  8. Delete the drug.

 

DOCK

SYBYL's docking functionality provides a real time approximation of the intermolecular energy of interaction between a pair of molecules (in kcals/mol), a useful tool for interactively identifying possible binding conformations. One molecule (stationary, by convention) is called the site, and the other is the ligand. Interactive output includes the total energy, the magnitude and direction of the overall force (for ligand atoms strongly interacting with the site), and the one site atom which is interacting most strongly.

  1. Load protein (hiv_protease.mol2) and drug (A77800.mol2). It is recommended that protein be loaded first.
  2. Position the ligand into the active site of the protein (you may wish to turn on shaded ribbon for the protein and spacefill for ligand).
  3. Prepare DOCK parameters.
  4. Begin docking.
  5. Move the ligand.
  6. Minimize docking energy
  7. End the docking operation.
  8. Warning: If you exit docking mode, then re-enter it, you may get an error message regarding a lack of memory. This is due to a memory allocation problem that cannot be avoided. The only work-around is to exit SYBYL and restart. Freeze the current view and save it to a database if you want to be able to restart exactly where you left off.

 

FlexiDock

Genetic algorithm-based Flexible Docking provides a means of docking ligands into protein active sites. FlexiDock works in torsional space, keeping bond lengths and angles constant. As large vdW interactions can only relax via bond rotation(s), optimization cannot alter chiral centers and bond stereochemistry. FlexiDock works on a protein/ligand pair. The protein backbone atoms are fixed in space, but the ligand is mobile (rotation/translation can be applied). Both the protein (sidechains only) and the ligand can contain a number of flexible bonds. However, to speed up calculations, FlexiDock considers only non-ring single and amide bonds as rotatable.

FlexiDock uses a genetic algorithm to determine the optimum ligand geometry. Genetic algorithms are relatively robust global optimizers, with performance requirements which scale well with increasing system size. The fitness function uses a subset of the Tripos force field: the van der Waals, electrostatic, torsional and constraint energy terms, and calculates the energy of the important atoms in the supermolecule.

  1. Set Up FlexiDock Structures
  2. Run FlexiDock.
  3. View docking results.
  4. View docked structure.
  5. Delete all molecules.

 

INVDOCK

A small molecule is flexibly docked into a cavity by a procedure involving multiple-conformer shape-matching alignment of the molecule to the cavity followed by molecular-mechanics torsion optimization and energy minimization on both the ligand and the binding region of the receptor. A new scoring method is used that performs binding competitive analysis in addition to the evaluation of molecular mechanics ligand–protein interaction energy.

  1. View docking results.
  2. View docked structure.