Protein-Ligand Docking: Methods and Applications, Schemes and Mind Maps of Developmental biology

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Protein-Ligand Docking

Alejandro Giorgetti

Outline

• Introduction to protein-ligand docking
• Searching for poses
• Scoring functions
• Assessing performance
• Practical aspects

Protein-ligand docking

• Predicts...
  • The pose of the molecule in the binding site
  • The binding affinity or a score representing the strength of binding
• A Structure-Based Drug Design (SBDD) method
• “structure” means “using protein structure”
• Computational method that mimics the binding of a ligand to a protein
• Given... Images from Charaka Goonatilake’s web page, Glen Group, Unilever Centre, Cambridge

Pose vs. binding site

• Binding site (or “active site”)
  • the part of the protein where the ligand binds
  • generally a cavity on the protein surface
  • can be identified by looking at the crystal structure of the protein bound with a known inhibitor
• Pose (or “binding mode”)
  • The geometry of the ligand in the binding site
  • Geometry = location, orientation and conformation
• Sometimes Protein-ligand docking is

for identifying the binding site

Drug Discovery Pipeline C. O’Driscoll. http://www.nature.com/horizon/chemicalspace/background/pdf/ odyssey.pdf

Computer-aided drug design (CADD) Known ligand(s) No known ligand Known protein structure Unknown protein structure Structure-based drug design (SBDD) Protein-ligand docking Ligand-based drug design (LBDD) 1 or more ligands

• Similarity searching Several ligands
• Pharmacophore searching Many ligands (20+)
• Quantitative Structure-Activity Relationships (QSAR) De novo design Need experimental data of some sort

Virtual screening

• Virtual screening is the computational or in silico

analogue of biological screening

• The aim is to score , rank or filter a set of structures

using one or more computational procedures

• Docking is just one way to do this (see next slide)
• It can be used
• to help decide which compounds to screen (experimentally)
• which libraries to synthesise
• which compounds to purchase from an external company
• to analyse the results of an experiment.

Virtual screening AR Leach, VJ Gillet, An Introduction to Cheminformatics

Final points

• Large number of docking programs available
  • AutoDock, DOCK, e-Hits, FlexX, FRED, Glide, GOLD, LigandFit, QXP, Surflex-Dock…among others
  • Different scoring functions, different search algorithms, different approaches
  • See Section 12.5 in DC Young, Computational Drug Design (Wiley
    2009. for good overview of different packages
• Note: protein-ligand docking is not to be confused with the field of protein-protein docking (“protein docking”)

Outline

• Introduction to protein-ligand docking
• Searching for poses
• Scoring functions
• Assessing performance
• Practical aspects

Ligand conformations

• Conformations are different three-dimensional structures of molecules that result from rotation about single bonds - That is, they have the same bond lengths and angles but different torsion angles
• For a molecule with N rotatable bonds, if each torsion angle is rotated in increments of θ degrees, number of conformations is (360º/ θ) N - If the torsion angles are incremented in steps of 30º, this is 12N - Having too many rotatable bonds results in “combinatorial explosion”
• Also ring conformations
  • Bioactive conformation may not be lowest energy ring conformer Taxol Images (from left): IUPAC Gold Book “chair, boat, twist”; “Wikipedia “Taxol”; Lakdawala et al, BMC Chem Biol , 2001 , 1 , 2.

The DOCK algorithm – Rigid docking

• The DOCK algorithm developed by Kuntz and co-workers is generally considered one of the major advances in protein–ligand docking [Kuntz et al., JMB, 1982 , 161 , 269]
• The earliest version of the DOCK algorithm only considered rigid body docking and was designed to identify molecules with a high degree of shape complementarity to the protein binding site.
• The first stage of the DOCK method involves the construction of a “negative image” of the binding site consisting of a series of overlapping spheres of varying radii, derived from the molecular surface of the protein AR Leach, VJ Gillet, An Introduction to Cheminformatics

The DOCK algorithm – Rigid docking AR Leach, VJ Gillet, An Introduction to Cheminformatics

• Ligand atoms are then matched to the sphere centres so that the distances between the atoms equal the distances between the corresponding sphere centres, within some tolerance.
• The ligand conformation is then oriented into the binding site. After checking to ensure that there are no unacceptable steric interactions, it is then scored.
• New orientations are produced by generating new sets of matching ligand atoms and sphere centres. The procedure continues until all possible matches have been considered.