Introduction to MoIecuIar Docking

Edelmiro Moman
PharmaceuticaI and MedicinaI Chemistry
SaarIand University

introduction to molecular docking edelmiro moman
DEFNTON
MoIecuIar docking tries to predict the structure of the
intermoIecuIar compIex formed between two or more
constituent moIecuIes.

introduction to molecular docking edelmiro moman
APPLCATONS
VirtuaI screening (hit identification)
Drug Discovery (Iead optimisation)
Prediction of K
A
(bioIogicaI activity ?)
Binding-site identification (bIind docking)
De-orphaning of a receptor
Protein - Protein (or Protein - NucIeic Acid) interactions
Structure-function studies
Enzymatic reactions mechanisms
Protein engineering

introduction to molecular docking edelmiro moman
The Protein Data Bank (PDB)
http://www.rcsb.org/

introduction to molecular docking edelmiro moman
Most typical case: Protein - Ligand docking
The final goal uses to be to predict the biological activity of a given ligand
Two different problems:
POSING
The process of determining whether a given conformation and orientation of a ligand
fits the active site. This is usually a fuzzy procedure that returns many alternative results.
SCORING
The pose score is a measure of the fit of a ligand into the active site. Scoring during the posing phase
usually involves simple energy calculations (electrostatic, van der Waals, ligand strain). Further
re-scoring might attempt to estimate more accurately the free energy of binding (G, and therefore K
A
)
perhaps including properties such as entropy and solvation.

introduction to molecular docking edelmiro moman
Nature Reviews Drug Discovery, 2004, 3, 935

introduction to molecular docking edelmiro moman
SCORNG FUNCTON N AUTODOCK
Molecular Mechanics Terms
van der Waals AG
vdW
W
vdW
_
i, f
( A
if
/ r
if
12
- B
if
/ r
if
6
)
Hydrogen Bonding AG
H-bond
W
H-bond
_
i, f
E(t) * ( C
if
/ r
if
12
- D
if
/ r
if
10
E
hbond
)
Electrostatics AG
elec
W
elec
_
i, f
( q
i
* q
f
) / ( c(r
if
) * r
if
)
Desolvation AG
desolv
W
desolv
_
i (C), f
(S
i
* J
f
* exp ( -r
if
2
/ (2 * o
2
) )
Change in Torsional Free Energy when the Ligand goes from Unbound to Bound
Torsional AG
tor
W
tor
N
tor

introduction to molecular docking edelmiro moman

introduction to molecular docking edelmiro moman
Posing and Scoring: FIexibIe docking aIgorithms
J. Mol. Graph. Model. 2007, 26, 198

introduction to molecular docking edelmiro moman

introduction to molecular docking edelmiro moman
MOLECULAR REPRESENTATIONS
Atomic
Surfaces
Grid

introduction to molecular docking edelmiro moman
PROTEIN FLEXIBILITY
MoIecuIar Dynamics
Usually in combination with other methods
Energy Minimisation
Monte CarIo
NormaI Modes
Rotamer Libraries
Protein EnsembIes (NMR, MD, NMA) / Protein EnsembIe Grids
Soft PotentiaIs

}
http://flipdock.scripps.edu/

introduction to molecular docking edelmiro moman
LIMITATIONS OF CURRENT DOCKING METHODOLOGIES
FIexibIe Iigands RotatabIe bonds CombinatoriaI expIosion

Entropic effects RotatabIe bonds
SoIvation / desoIvation Accurate computation is expensive
Water moIecuIes (and ions)
Tautomers
Protein fIexibiIity Induced fit
Specificity of binding Understanding important interactions
(currently larger ligands are favoured by the scoring functions)
Pharmacokinetic effects, allosteric effects, biomolecule-biomolecule
interactions (molcecular context), etc.

introduction to molecular docking edelmiro moman
DOCKING SOFTWARE
Proteins: Structure, Function and Bioinformatics 2006, 65, 15.

introduction to molecular docking edelmiro moman
RESOURCES:
Protein Protein nteraction Website (docking software):
http://www.imb-jena.de/jcb/ppi/jcb_ppi_software.html
Structural Biology Software Database:
http://www.ks.uiuc.edu/Development/biosoftdb/biosoft.cgi
Molecular Docking Web:
http://mgl.scripps.edu/people/gmm/
Molecular Docking Servers:
http://www.dockingserver.com/web
http://bioinfo3d.cs.tau.ac.il/PatchDock/
My Website:
http://www.edelmiromoman.eu/
AutoDock GUs: AutoDockTools (ADT), BDT, DOVS

introduction to molecular docking edelmiro moman
CONCLUDING REMARKS
MoIecuIar modeIIing is about READING !!!
Inspect aII avaiIabIe structures of your protein: check for aIternative
conformations, R factors, Iigands; become famiIiar with your binding site
CarefuIIy consider tautomerism, protonation, waters, X-ray resoIution, etc.
AIso Iook to proteins of the same or reIated famiIies / functions
CoIIect aII the reIevant empiricaI data: site-directed mutagenesis, Iigands,
affinity / inhibition constants, etc.
CriticaIIy anaIyse aII this stuff in view of existing (and your own)
hypotheses
You are ready for modeIIing ! (docking is just the beginning)
Find the right baIance between simuIations and experiments


www.edelmiromoman.eu edelmiro moman
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