Post on 18-Aug-2021
Unit 2: Ligand-Protein Docking
2
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
4
What is Protein-Ligand Docking?
• Definition:
Computationally predict the structures of protein-ligand
complexes from their conformations and orientations.
• Importance of complexes- structure -> function
5
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
6
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
7
Docking Flowchart
8
Which Compound Library?• Commercially-available screening collections are important sources
for identifying hits by virtual screening(VS)
9
> 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?
10
11
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
14
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
16
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
17
Genetic Algorithms
18
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?
19
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
21
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
25
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
27
Docking … complications
• Correct binding pose
• Incorrect ranking
• Differentiate correct / incorrect poses
• Differentiate correct / incorrect hits
• Free-energy calculations
– Protein-ligand interactions
– Binding affinity
28
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.
29
• Virtual screening: Enrichment
• Lead optimization: analogues
• MD Simulations
• Free energy calculations
30
Docking score
Experience
Intuition