What is Docking?

BL5203: Molecular Recognition & Interaction BL5203: Molecular Recognition & Interaction

Lecture 5: Drug Design Methods Lecture 5: Drug Design Methods Ligand-Protein Docking (Part I)Ligand-Protein Docking (Part I)

Prof. Chen Yu ZongProf. Chen Yu Zong

Tel: 6874-6877Tel: 6874-6877Email: Email: [email protected]://xin.cz3.nus.edu.sg

Room 07-24, level 7, SOC1, Room 07-24, level 7, SOC1, National University of SingaporeNational University of Singapore

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What is Docking?What is Docking?

• Given two molecules find their correct association:

+

=

Recep

tor Ligand

T

Complex

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General Protein–Ligand BindingGeneral Protein–Ligand Binding• Ligand

- Molecule that binds with a protein

- DNA, drug lead compounds, etc.

• Protein active site(s)- Allosteric binding

- Competitive binding

• Function of binding interaction

- Natural and artificial

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What is Protein-Ligand What is Protein-Ligand Docking?Docking?

• Definition: Computationally predict the structures of protein-ligand

complexes from their conformations and orientations. The orientation that maximizes the interaction reveals the most accurate structure of the complex.

• Importance of complexes- structure -> function

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Example: HIV-1 ProteaseExample: HIV-1 Protease

Active Site(Aspartyl groups)

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Example: HIV-1 ProteaseExample: HIV-1 Protease

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PDBfiles

Surface Representation

Patch Detection

Matching Patches

Scoring & Filtering

Candidatecomplexes

Docking StrategyDocking Strategy

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Issues Involved in DockingIssues Involved in Docking

• Protein Structure and Active Site- Assumed knowledge (PDBs, Homology modeling etc.)

- PROCAT database: 3d enzyme active site templates

• Ligand Structure- Pharmacophore (base fragment) in potential drug compound

- well known groups

• Rigid vs. Flexible- In solution or in vaccume

- Structure fixed, partly fixed, modeling of flexibility

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Algorithmic Approaches to DockingAlgorithmic Approaches to Docking

• Qualitative– Geometric– Shape complementarity and fitting

• Quantitative– Energy calculations– Determine global minimum energy– Free energy measure

• Hybrid– Geometric and energy complementarity

– 2 phase process: soft and hard docking

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..Design of HIV-1 Protease InhibitorDesign of HIV-1 Protease Inhibitor

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Scoring in Ligand-Protein DockingScoring in Ligand-Protein Docking

Potential Energy Description:

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Preprocessing Preprocessing • Determine internal representation

- Convert coordinates of both molecules from PDB files

- e.g. Michael Connolly’s MS program (www.biohedron.com)

- dot surface

- AutoGrid

- 3d grid (array) with discrete values

- often used in rigid docking

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Some techniquesSome techniques

• Surface representation, that efficiently represents the docking surface and identifies the regions of interest (cavities and protrusions)

• Connolly surface• Lenhoff technique• Kuntz et al. Clustered-Spheres• Alpha shapes

• Surface matching that matches surfaces to optimize a binding score:

• Geometric Hashing

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Surface RepresentationSurface Representation

• Dense MS surface (Connolly)

• Sparse surface (Shuo Lin et al.)

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Surface RepresentationSurface Representation

• Each atomic sphere is given the van der Waals radius of the atom

• Rolling a Probe Sphere over the Van der Waals Surface leads to the Solvent Reentrant Surface or Connolly surface

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Lenhoff techniqueLenhoff technique

• Computes a “complementary” surface for the receptor instead of the Connolly surface, i.e. computes possible positions for the atom centers of the ligand

Atom centers of the ligand

van der Waals surface

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Kuntz et al. Clustered-SpheresKuntz et al. Clustered-Spheres• Uses clustered-spheres to identify cavities on the receptor and

protrusions on the ligand• Compute a sphere for every pair of surface points, i and j, with

the sphere center on the normal from point i• Regions where many spheres overlap are either cavities (on the

receptor) or protrusions (on the ligand)

i

j

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Alpha ShapesAlpha Shapes

• Formalizes the idea of “shape”• In 2D an “edge” between two points is “alpha-exposed” if

there exists a circle of radius alpha such that the two points lie on the surface of the circle and the circle contains no other points from the point set

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Alpha Shapes: ExampleAlpha Shapes: Example

Alpha=infinity

Alpha=3.0 Å

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Surface MatchingSurface Matching

• Find the transformation (rotation + translation) that will maximize the number of matching surface points from the receptor and the ligand

First satisfy steric constraints…• Find the best fit of the receptor and ligand using only geometrical

constraints

… then use energy calculations to refine the docking• Select the fit that has the minimum energy

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Docking ProgramsDocking Programs

More information in: http://www.bmm.icnet.uk/~smithgr/soft.html

The programs are:

• DOCK (I. D. Kuntz, UCSF)

• AutoDOCK (Arthur Olson, The Scripps Research Institute)

• RosettaDOCK (Baker, Washington Univ., Gray, Johns Hopkins Univ.)

• INVDOCK (Y. Z. Chen, NUS)

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DOCK as an ExampleDOCK as an Example

DOCK works in 5 steps:• Step 1 Start with 3D coordinates of target receptor• Step 2 Generate molecular surface for receptor• Step 3 Generate spheres to fill the active site of the

receptor: The spheres become potential locations for ligand atoms

• Step 4 Matching: Sphere centers are then matched to the ligand atoms, to determine possible orientations for the ligand

• Step 5 Scoring: Find the top scoring orientation

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1 2

3

- HIV-1 protease is the target receptor- Aspartyl groups are its active side

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4 5

• Three scoring schemes: Shape scoring, Electrostatic scoring and Force-field scoring• Image 5 is a comparison of the top scoring orientation of the molecule thioketal with the orientation found in the crystal structure

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The DOCK AlgorithmThe DOCK Algorithm

Two steps in rigid ligand mode:

Orienting the putative ligand in the siteGuided by matching distances, between pre-defined site points on the target to interatomic distances of the ligand. The RT matrix is used for the transform of the ligand.

Scoring the resulting orientationEach orientation is scored for each quality fit. The process is repeated a user-defined number of orientations or maximum orientations

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.. .

.

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. .

N

NH

N

SO

F

.. .

N

NH

N

SO

F

.

N

NH

N

SO

F

N

NH

N

SO

F

1. Define the target binding site points.

2. Match the distances.

3. Calculate the transformation matrix for the orientation.

4. Dock the molecule.

5. Score the fit.

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Site Points Generation in DOCKSite Points Generation in DOCK

• Program SPHGEN identifies the active site, and other sites of interest.

• Each invagination is characterized by a set of overlapping spheres.

• For receptors, a negative image of the surface invaginations is created;

• For a ligand, the program creates a positive image of the entire molecule.

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The MatchingThe MatchingCan be directed by 2 additional features:

• Chemical matching - labeling the site points such that only particular atom types are allowed to be matched to them.

• Critical cluster - subsets of interest can be defined as critical clusters, so that at least one member of them will be part of any accepted ligand “match”.

Increase in efficiency and speed due to elimination of potentially less promising orientations!

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Other Docking programsOther Docking programs

AutoDock– AutoDock was designed to dock flexible ligands into receptor

binding sites– The strongest feature of AutoDock is the range of powerful

optimization algorithms available

RosettaDOCK– It models physical forces and creates a very large number of

decoys – It uses degeneracy after clustering as a final criterion in decoy

selection

INVDOCK– Docking strategy and algorithm similar to DOCK, but with the

capability of finding the receptors to which a molecule can bind to.

Documents

What is Docking?