Docking

Olivier Taboureau
otab@cbs.dtu.dk

Systems Chemical Biology CBS Department of Systems Biology

Plan

Docking and scoring: deniAon. Dierent factors to consider. How to analyze and to evaluate the accuracy of a docking . Flexible docking, an extension of the classical docking. Examples.

Docking deniAon
In molecular modeling, docking aims to predict the posiAon and orientaAon of a ligand (or small molecule) when it is bound to a protein, receptor or enzyme. The orientaAon that maximizes the interacAon reveals the most accurate structure of the ligand-protein complex.

IdenAcaAon of best soluAons are done using a scoring funcAon

Why/When Docking & Scoring

Play an important role in the raAonal drug design and in the discovery of new medicaAons.

It can give some interpretaAon of experimental data (i.e. Dierence in binding anity) and assume design of new ligands.

It needs a 3D structure of the protein (X-ray, NMR, homology,)

Force of binding
Force of binding
KA KD

Paq + Laq
H2 O

PLaq

G = H TS = RT lnKA
Protein-Ligand complex Ligand KA KD

Protein

Complementarity, desolvation, conformational changes

Slide from L. Olsen

Important for binding

Factor aectant G
G = H TS = RT lnKA
Complementarity (H)
ElectrostaAc/polar interacAons vdW interacAons (dispersion/repulsive)

H2 O SolvaAon/DesolvaAon (H, S)
H-bonds are formed/disrupted: (H) Ordered/disordered H2O: (S)

ConformaAonal changes (H, S)

Penalty for distorAng the ligand (H) Changes in protein (H) Torsional restricAons (S)

KA : 10-2 10-12 M G : -10 to -70 kcal/mol

Slide from L. Olsen

Factor aectant G
Intramolecular forces (covalent) - Bond lengths - Bond angles - Dihedral angles Intermolecular forces (non covalent) - ElectrostaAcs - Dipolar interacAons - Hydrogen bonding - Hydrophobicity - Van der Waals Keep in mind H and S work against each other

Design of drugs
H-bonding all H-bonding groups in the ligand must make H-bonds when bound. H-bond geometry gives ligand specicity. contribute lidle to ligand anity. G = H TS
makes the ligand soluble.

Hprotein-ligand

.. .. ..
.. ..

vdW interacAon contribute lidle to anity. steric clashes must be avoided. Hydrophobic eect promote anity. Hydrophobicity may give non-specic binding. makes the ligand non-soluble. Changes in conformaAon High anity ligands: max. penalty of 3 kcal/mol Many rotatable bonds should be avoided

Hdisplacing waters from protein Hdisplacing waters from ligand Hwater bridges G ..

Sentropy from hydrophobic interacAons Srestricted rotaAonal torsions

Slide from L. Olsen

Example of energy for one hydrogen bond

Protein
protein N H + H H O H O ligand N H O protein-ligand complex + H H O H O H

Ligand

NH O:

... ...

:OH2 HOH HN

NH + OH2 O: + HOH O:
...

4.2 Kcal/mole 3.4 Kcal/mole -3.2 Kcal/mole -4.5 Kcal/mole -0.1 Kcal/mole

O: +

HN OH2

HOH + OH2

HOH

...

Overall energy change Protein-ligand complex

Slide from L. Olsen

Scoring funcAons
Molecular mechanics force eld-based AniAes are esAmated by summing the strength of intermolecular van der Waals and electrostaAc interacAon between all atom of the molecule-protein complex. - CHARMM, AMBER Empirical methods-based Based on counAng the number of various types of interacAons between the two binding partners (hydrogen bond, hydrophobic) - ChemScore, GlideScore, AutoDock Knowledge-based methods-based Based on staAsAcal observaAons of intermolecular close contacts in large 3D databases (CSD or PDB) which are used to derive potenAals of mean force - PMF, DrugScore

force eld-based

empirical-based
Master equation G = GSolv + GConf + GCompl + GMotion + ........ = ci Gi

Changes in free energy G when binding a ligand to a protein:

GSolv : SolvaAon GConf = GConf,protein + GConf, ligand : ConformaAonal GCompl : Complementarity between protein and ligand (vdW, H-bonds, electrostaAcs) GMoAon = Grot + Gt/r + Gvib : TranslaAonal/rotaAonal/vibraAonal

knowledge-based
Docking Scoring

Large data samples The general idea is:

General rules and principles

InteracAons that are ogen found are considered adracAve for binding PotenAals are developed from radial disAbuAon funcAons gij(r), r is the distance between atom i and j

Comments :
G ~ occurence of atom-atom pairs ? Less intuiAve Unusual ligand atoms will decrease the score ? ProtonaAon of residues ? Incorporate all eects implicitly even those not fully understood No training set
Slide from L. Olsen

Algorithms used while docking

Fast shape matching (e.g., DOCK and Eudock), Incremental construcAon (e.g., FlexX, Hammerhead, and SLIDE), Tabu search (e.g., PRO_LEADS and SFDock), GeneAc algorithms (e.g., GOLD, AutoDock, and Gambler), Monte Carlo simulaAons (e.g., MCDock and QXP),

Some sogwares

Software FlexX GOLD AutoDock Glide PMF DrugScore

Docking algorithm
Incremental construction

Scoring function
Empirical

Availability
Via MOE or separatly

Genetic

vdW (internal, external), H-bonds (charge-charge), torsional penalty

Genetic or MD Empirical

GOLD scoring funcAon Seperate program. Not Empirical expensive

Seperate program. Free

MC

Empirical GLIDE scoring funcAon Via Maestro (~ChemScore) Knowlegde-based Via Sybyl

Lipophilic, H-bonds, charge-charge, torsional penalty, solvaAon

%

Knowlegde-based

Via Sybyl

Performance good in different tests

EvaluaAon of the docking, example with PPAR inhibitors

Examine the docked structures one by one QuanAtaAve measure for the quality of the docking: RMSD with respect to the experimental binding mode

RMSD = Root Mean Square Distance Unit = length (e.g. )

di : distance between atom i in the docked and reference stucture

Docking of the same molecule as the X- ray complex structure Score = -16 kcal/mol , rmsd = 0,001

Docking of a new molecule. Score = -8,3 kcal/mol, rmsd = 0,014

EvaluaAon of the docking, example with PPAR inhibitors -2

Hbonds between ligands and proteins are shown in green.

ApplicaAon of docking and scoring

3D Pharmacophore 3 new inhibitors identified Organic synthesis Database search Exp. IC50 Docking of the hits Selection of compounds

Example of docked structure

3D Pharmacophore

Slide from L. Olsen

Protein Flexibility
A protein is not staAc but can adopt dierent conformaAon according of his state (binding- non binding or depending of the substrate/inhibitor.

Methods for accommodaAng protein exibility in docking: - The ensemble approach - The induced t approach

Protein Flexibility

Goh, C.-S. et al. Curr. Opin. Struct. Biol. 14, 104-109 (2004)

Teague, S.J. Nature Reviews 2, 527-541 (2003)

Protein Flexibility

Teague paper lists pharmaceuAcally relevant exible targets (some 30 systems!) Consequences of protein exibility for ligand design
One site, several ligand binding modes possible

Docking method to incorporate protein exibility Ensemble docking

Docking to individual protein structures, or parts of protein structures ensemble docking Docking to a single average structure sog docking HOW? Experimentally derived structures NMR or X-ray structures ComputaAonally derived structures Molecular dynamics Simulated annealing Normal mode propagaAon

FlexE
- Similar parts of the protein structures are merged - Dissimilar parts of the protein are treated as separate alternaAves

Docking method to incorporate protein exibility

Induced-Fit Docking Methods
Allow protein conformaAonal change at the same Ame as the docking proceeds.

TM4 R152 I165 V343

Y95 Y176 F341 D98 G100 F335 I172 S438

A169 F170 T439 G442 L443 A173 N177

Induced-Fit Docking - GLIDE

Residues suscepAble to have a role in the binding change of a compound are mutated to ALA, before the docking and added again for the renement of the interacAon.
A441G CIT: 2.5x gain of funcAon CIT with ears: 2x gain of funcAon

A441G V343S V343N

V343S CIT: 4.5x gain of funcAon Des-CN: 4.9x gain of funcAon [Des-F: 7.4x gain of funcAon] V343N CIT: 3.5x gain of funcAon Des-CN: 35.5x gain of funcAon [Des-F: 3.8x gain of funcAon]

S438T
S438T CIT: 175x loss of funcAon Monomethyl: 3.5x loss of funcAon

A173S
A173S CIT: 4.5x gain of funcAon Des-F: 16.5x gain of funcAon

Quantum-mechanics based scoring funcAon -PerspecAve

HQM : Semi-empirical energy funcAon (AM1, linear scaling) GMM,VdW : Dispersion (-R-6 term) from Amber force-eld GQM,solv : PB/SCRF method SDisp.,HOH : Displaced water molecule pre-bound to protein SConf.,ligand : 1 kcal/mol per rotable bond

*Raha and Merz, J. Am. Chem. Soc., 126, 1020-1021, 2004

Slide from L. Olsen

Summary
Docking: A tool to look on the position of a ligand inside the protein. Scoring: A measure for how well the ligand fits into the protein Empirical G = GSolv + GConf + ... (depend also on the force field used)
Knowledge-based: Large data samples -> General rules And many other approaches Flexible docking: An alternative procedure to take into account the protein

flexibility.
Ensemble

Induce Fit

Quantum mechanic based: Still time consuming and not yet ready for virtual screening QUESTIONS