Molecular DockingMolecular Docking

Chao-Sheng Cheng

Department of Life Science,Department of Life Science,National Tsing Hua University National Tsing Hua University

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Computational ligand design

Target StructureTarget Structure

Ligand-based approachesLigand-based approaches Structure-based approachesStructure-based approaches

knownunknow

(Pharmacophore + QSAR) (Docking; De novo design)

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Computational ligand designTwo different strategies:

Ligand-based (analog-based) design Relies on a set of known ligands and is particularly valuable if

no structural information about the receptor is available.

Structure-based (target-based) design Usually starts with the structure of a receptor site, such as the

active site in a protein. This structure can be generated from direct experimentation or

can be deduced from experimental structures through homology modeling

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Structure-based (target-based) design

(Krumrine et al., 2003)

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Docking is an energy-based operation for exploring the binding modes of two interaction molecules.

Give the 3D structure of a protein target, compuonds can be designed to fit in a cavity, which is called "docking".

The treatment ends when a minimum of energy is obtained for the complex.

Definition of Docking

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Docking Goal

1. To build the binding model between ligand and protein

2. To clarify the critical residues which involve in ligand binding

3. To engineer the protein by mutagenesis

4. To develop a drug from a compound database

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Before Docking

( target site)

bind site ( shape) hydrophobic sites (H),

hydrogen bond donors (D) and acceptors (A) (Flexible)

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Before Docking

Where

Whatdocking(conformation)?

How??

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Docking Require

Ligand structure

Protein structure

Docking software

Ligand: XK-263

Protein: HIV-1 Protease (1hvr)

Software: AutoDock version 2.4

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Docking Methods Some common searching algorithms include

Molecular dynamics Monte Carlo methods [AutoDock, ProDock, MCDOCK...] Genetic algorithms [GOLD, AutoDock, DARWIN...] Fragment-based methods [FlexX and DOCK] Point complementary methods [FTDOCK, FLOG...] Distance geometry methods [DockIt] Tabu searches [PRO LEADS] Systematic searches

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Force Field Models Force fields are usually employed to generate accurate

predictions to complex problems by interpolating and extrapolating from relatively simple experimental set of molecules.

Classical force field models AMBER, CHARMM and CVFF.

Second generation force field models CFF and COMPASS.

Generalized force field models ESFF and UFF.

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Docking Flowchart

InputInput

OutputOutput

DockingDocking

LimitationLigand structureProtein structure

AutodockDockLudiGramm

Complex structure informationAnalysis ProSall, SWISS PDB ViewerEvaluation

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Docking Flowchart

InputInput

OutputOutput

DockingDocking

LimitationLigand structureProtein structure

AutodockDockLudiGramm

Complex structure informationAnalysis ProSall, SWISS PDB ViewerEvaluation

For Input Data:

Protein must be high resolution!

B factors

NMR(Poorly constrained regions)

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Docking Flowchart

InputInput

OutputOutput

DockingDocking

LimitationLigand structureProtein structure

AutodockDockLudiGramm

Complex structure informationAnalysis ProSall, SWISS PDB ViewerEvaluation

For Output Data:

(active sites)

(Geometry)

(potential energy)

(ligand)

(bioassay)(affinity)

scoring function

Root mean square deviation (RMSD)QSAR (Quantitative Structure-Activity Relationship)

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Evaluation

Analysis

Complex form (1UVB) Complex form (1UVB) with two lipidswith two lipidsComplex form (1UVC) Complex form (1UVC) with one lipidwith one lipid

Total volume (ATotal volume (A33))CavityCavity

Vander Waals Vander Waals (A(A33))

ProbeProbe--accessibleaccessible(A(A33))

Free formFree form 1623016230 278.6278.6 72.1672.16Complex formComplex formwith one lipidwith one lipid

1624016240 274.5274.5 82.1182.11

Complex form Complex form with two lipidswith two lipids 1668016680 11381138 237237

Superposition of structurescholesterol-nsLTP2 (red) and nsLTP2 (blue)

1. The major difference in the two conformations is observed at theloop between helices I and II, where the structure is stretched out approximately 3.10 .

2. Residues with larger chemical shift perturbations were also represented with yellow color.

RMSD: 1.57

MolScript

Leu8, Ile15, Phe39, Tyr45, Tyr48, Val49, Pro52, Ala54, Val58, Leu65 and Pro66

DS ViewerPro Ligplot

1. Various residues involved in the sterol binding are colored in green. Most of these residues are located around helices I, IV and V.

2. Comparing the theoretical docked structure and experimental NMR results, the residues directly interacting with the ligand are Leu8, Ile15, Phe39, Tyr45, Tyr48, Val49 and Val58.

SWISS PDB Viewer1.Distance/angle2.Ribbon3.Ramachandran plot4.Mutation/rotamer5.Superimpose6.Compute H-bond/energy7.Energy minimization8.Cavity

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Docking Software

Molegro

http://www.molegro.com/

Molegro Virtual Docker - Overview Overview

Molegro Virtual Docker is an integrated platform for predicting protein - ligandinteractions. Molegro Virtual Docker handles all aspects of the docking process from preparation of the molecules to determination of the potential binding sites of the target protein, and prediction of the binding modes of the ligands.

The Molegro Virtual Docker (MVD) has been shown to yield higher docking accuracy than other state-of-the-art docking products (MVD: 87%, Glide: 82%, Surflex: 75%, FlexX: 58%).

Molegro Virtual Docker provides: High docking accuracy: the docking engine has been proven to correctly

identify binding modes with high accuracy. Molegro Virtual Docker has been shown to outperform other docking programs with regard to identification of correct binding modes (see the technology pages for more information).

Easy-to-use interface: the built-in wizards enable the user to easily setup and perform docking runs. Advanced visualization and analysis tools are provided to examine ligand-receptor interactions and fine-tune found docking solutions.

Cross-platform: supported on Linux, Windows and Mac, allowing easy interoperability between platforms.

The main user interface

Basic Tutorials

Tutorial 1: A Simple Docking Run Tutorial 2: Inspecting the Docking

Results Tutorial 3: Visualization in MVD

Tutorial 1: A Simple Docking Run

Import molecules into Molegro Virtual Docker (MVD).Detect potential binding sites and setup the search

space. Run a docking simulation using the Docking Wizard. Inspect the docking results using the Pose Organizer.

Import molecules into MVD Require:

3D structure of a receptor 3D structure of one or more ligands Formats: PDB, Mol2, and SDF

The exact 3D conformation of the ligands is not important - the torsional angles in the ligand will be determined during docking (but needs the ligand structure with proper bond lengths & bond angles)

In order for a docking simulation to succeed, various properties of the molecules must be assigned.How the atoms are chargedThe order and type of the bonds

This tab shows warnings from the molecule parsing.Careful to inspect the warningsSome warnings are harmless:Some proteins are cropped, causing MVD to warn about residues having an insufficient number of atoms

1HVR ok

workspace

1. Turn on/off using checkbox

Create protein surface

Pay attention on our ligand

Some bonds in the ligand are colored greenflexible during the docking

Redheld fixed during the simulation (ring conformations are

not changed during docking)

Detect potential binding sites and setup the search space

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Run a docking simulation using the Docking Wizard

Reference ligand- allow us to monitor the RMSD to the best found psoe while docking

Define scoring function & search space

Search algorithm

Best poses for the current ligand

Best found score for the current run

Tutorial 2: Inspecting the Docking Results

Show all & dynamic update

Select here

Right button of mouse

Tutorial 3: Visualization in MVD

Navigating in the 3D view. Using Visualization Presets and Styles. Work with surfaces and backbone

representations. Use Clipping Planes, Labels, and the

Sequence Viewer.

Hydrogen bond interaction

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surface

Clipping plane

backbone

Show sequence

Right mouse button to select a.a.

visualization