Unit 2: Ligand-Protein Docking

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What is Docking?

• Given two molecules find their correct

association:

+

=

T

3

General Protein–Ligand Binding

• Ligand

• Protein active site(s)- Allosteric binding

- Competitive binding

• Function of binding

interaction

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What is Protein-Ligand Docking?

• Definition:

Computationally predict the structures of protein-ligand

complexes from their conformations and orientations.

• Importance of complexes- structure -> function

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Issues Involved in Docking

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

- Catalytic site atlas: 3d enzyme active site templates

• Ligand- Chemical structure

- Pharmacophore: well known groups

• Rigid vs. Flexible- Structure fixed, partly fixed, modeling of flexibility

• In vacuum or with solvent

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Algorithmic Approaches to Docking

• Qualitative– Geometric

– Shape complementarity and fitting

• Quantitative– Energy calculations

– Determine global minimum energy

• Hybrid– Geometric and energy complementarity

– 2 phase process: soft and hard docking

Strategic importance of docking

Scientific reasons

• Increasing number of relevant macromolecular targets (500 -> 6,000)

• Increasing number of protein 3D structures (X-ray, NMR)

• Better knowledge of protein-ligand interactions

• Development of chem-and bio-informatic methods

• Increasing computing facilities

Economic reasons

• High cost of high-throughput screening (HTS)

• Increase the ratio # of active molecules (hits)/ # of tested molecules

Applications

• Identifying/optimize ligands for a given target

• Identifying target(s) for a given ligand

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Docking Flowchart

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Which Compound Library?• Commercially-available screening collections are important sources

for identifying hits by virtual screening(VS)

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> 3,000,000 million compounds availableSiroiset al. Comput. Biol. Chem.(2005) 29, 55-67.

Which docking tool?

• Over 65 docking tools around

• Which one to use?

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Which docking tool?

Moitessier et al. (2008) Br J Pharmacol, 153: S7-26

12Moitessier et al. (2008) Br J Pharmacol, 153: S7-26

Which docking tool?

13Sousa et al(2006) Proteins, 65:15-26.

Docking methods

Docking means: Find quickly (< 1 min) :

- possible bound conformations of a ligand

- respective orientation of the ligand vs. protein

Step 1. Conformational sampling of the ligand in the

protein, active site

Step 2. Scoring each pose with a scoring function

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Conformational sampling

methodsRigid body docking (DOCK, FRED)

15Moitessier et al. (2008) Br J Pharmacol, 153: S7-26

Conformational sampling

methods

Stochastic methods: MC, MD, GA

Monte Carlo (MC): Glide

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Moitessier et al. (2008) Br J Pharmacol, 153: S7-26.

Monte Carlo

• Step 1: Create a parametric model, y = f(x1, x2, ..., xq)

• Step 2: Generate a set of random inputs, xi1, xi2, ..., xiq

• Step 3: Evaluate the model and store the results as yi

• Step 4: Repeat steps 2 and 3 for i = 1 to n

• Step 5: Analyze the results using histograms, summary

statistics, confidence intervals, etc

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Genetic Algorithms

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Algorithm is started with

a set of

solutions (represented

by chromosomes)

called population

Which scoring function?

• Over 30 scoring functions around

• Which one to take?

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Which scoring function?

20Moitessier et al. (2008) Br J Pharmacol, 153: S7-26

Scoring functions

Two aims:

• Rank docking poses by decreasing

interaction energy

• Predict the binding free energy (affinity) of

compounds

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DGbinding = RT log KD

DGbinding = f (interactions)

Molecular Design

Originated in Drug Design

Agricultural, Veterinary, Human Health

Guest - Host Chemistry

Ligands for Inorganic Complexes

Materials Science

» Polymer Chemistry

» Supramolecular Chemistry

» Semi-conductors

Information Technology

Store and Retrieve

Molecular Structures and Properties

Efficient Retrieval Critical Step

Multi-million $ industry

Pharmaceutical Industry

» $830 million to bring a new drug to market

» Need to find accurate information

» Shorten time to market, minimize mistakes

CAMD

Determine Structure of Guest or Host

Build a model of binding site

Search databases for new guests (or hosts)

Dock new guests and binding sites

Predict binding constants or activity

Synthesize guests or hosts

Lennard-Jones Potential

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Docking

• Binding pose prediction

• Correct prediction of activity (“good

ranking is enough”)

• Shape & electrostatics

– Conformational search

– More accurate scoring functions

– Improved electrostatics, VdW, solvation,

entropy, etc. 26

Docking … complications

• Resolution of X-ray structures

• Induced fit

• Flexibility of the receptor

• Functional water molecules

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Docking … complications

• Correct binding pose

• Incorrect ranking

• Differentiate correct / incorrect poses

• Differentiate correct / incorrect hits

• Free-energy calculations

– Protein-ligand interactions

– Binding affinity

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Docking … scoring functions

• Force-field based: Molecular mechanics force fields usually quantify the

sum of two energies, the receptor–ligand interaction energy and internal ligand energy most only

consider a single protein conformation, which permit omit the calculation of internal protein

energy,which greatly simplifies scoring.

• Empirical: These scoring functions are fit to reproduce experimental data, such as

binding energies and/or conformations, as a sum of several parameterized functions.

• Knowledge-based: Designed to reproduce experimental structures rather

than binding energies. protein–ligand complexes are modelled using relatively simple atomic

interaction-pair potentials.

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• Virtual screening: Enrichment

• Lead optimization: analogues

• MD Simulations

• Free energy calculations

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Docking score

Experience

Intuition