Professional Documents
Culture Documents
Antonio Morreale
Federico Gago
Departamento de Farmacologa
Universidad de Alcal, Madrid
Paul Ehrlich
MAGIC
BULLETS
(-)
electrostatic complementarity
in binding sites
(+)
HIV-1 protease
efavirenz
Human mitochondrial
thymidine kinase
http://lorentz.immstr.pasteur.fr/nma/index.php
http://loschmidt.chemi.muni.cz/caver/
Drug + Receptor
Drug-Receptor
koff
Ligand-Receptor
% of maximal effect
Ligand + Receptor
kon
Receptor
Drug
A A
Drug B B
Receptor
Drug C C
Receptor
Drug D D
Receptor
Drug E E
Receptor
log [concentration M]
Binding Energy
Binding Constant
G (kcal/mol)
Kd
0.5
1.0
1.5
2.0
2.5
3.0
2x
5x
13x
29x
68x
158x
G = H TS = 2.303 RT log Kd
Ajay, Murcko MA. Computational methods to predict binding free energy in ligand-receptor
complexes. J. Med. Chem. 1995, 38, 4953-4967
G binding = G LR (G R + G L )
implicit
solvent
explicit
solvent
binding
L
R
3D protein structures
(templates for model building)
Comparative modelling
Virtual libraries
(diverse compounds,
chemical inventory)
Sequences of novel
therapeutic targets
High-throughput docking
(in silico screening of compounds on
3D structures of targets)
Hits
Structure-based analog design
(design of modified hits using 3D protein-ligand
complexes and computer simulations)
Leads
Validated Targets
+
Combinatorial Chemistry /
Natural Products Libraries
THE DOCKING
PROBLEM
Ligand-Receptor Complexes
Virtual Screening
Ligand
Chemical
Library
Protein
(rigid)
Docking
Evaluation
MM Force Fields
Empirical Data
Potentials of Mean Force
Search engine
Systematic Sampling
Stochastic Sampling
Deterministic Sampling
Pose + Score
Objective of VS:
candidate prioritization
Docking software use according to number of citations in ISI Web of Science 2005
Donepezil
Decamethonium
Acetylcholine
Huperzine
Tacrine analogue
Ensemble
docking
six degrees
of freedom
binding score
Huang SY, Zou X: Ensemble docking of
multiple protein structures: considering
protein structural variations in molecular
docking. Proteins 2007, 66:399-421.
Molecular Mechanics
Also a scoring function for docking
BONDING TERMS
Eangle =
1
2
(
)
0
2
angles
1
2
Ebonds = kb (b b0 )
bonds2
Edihedral =
1
k d [1 + cos( 0 )]
dihedrals 2
NON-BONDING TERMS
E electrosta tic
1
=
4 0
ij
qi q j
rij
ELennardJones
A ij Bij
= 12 6
rij
ij rij
repulsive
i
attractive
+
i
Poisson equation:
(r ) =
Poisson-Boltzmann equation:
s
+
- +
4(r )
[ (r ) (r )] k ' (r ) = 4(r )
R
Gsolv
+
- +
RL
G int
-+
-s+
L
Gsolv
- +
-+
RL
G int
Desolvation effects
Directional effects of hydrogen bonds
Dispersive interactions
C. Prez & A. R. Ortiz
J. Med. Chem. 44, 3768-3785 (2001)
SMILES
Simplified Molecular Input Line Entry Specification
Rules
1. Atoms are represented by atomic symbols: B, C, N, O, F, P, S, Cl, Br, and I.
2. Double bonds are `=', triple bonds are `#'.
3. Branching is indicated by parentheses.
4. Ring closures are indicated by pairs of matching digits.
Examples
Depiction
SSMILES
Name
Remark
methane
CCO
ethanol
CC(=O)O
acetic acid
C1CCCCC1
cyclohexane
http://www.daylight.com/dayhtml/doc/theory/theory.smiles.html
SMARTS
SMiles ARbitrary Target Specification
A language for specifying substructural patterns in molecules
The SMARTS line notation is expressive and allows extremely precise
and transparent substructural specification and atom typing:
1. Atomic properties: Aliphatic carbon [C], aromatic carbon [c], any carbon [#6] or [C,c]...
2. Bonds: (single), = (double), # (triple), : (aromatic), and ~ (any).
3. Connectivity: [CX4] matches a carbon atom with bonds to 4 other atoms.
4. Cyclicity: smallest set of smallest rings (SSSR).
5. Logical operators: and or , ; & ! (not)
Applications:
1. Definition of substructural filters e.g. to identify undesirable compounds
2. Definition of bond types in RECAP (Retrosynthetic Combinatorial Analysis
Procedure)
3. Use in several programs: Leatherface (molecular editor), ALADDIN (pharmacophore
matching), etc
Available Chemicals
Directory
World Drug Index
MedChem Database...
compound
databases
REOS
druglikeness
filters
undesired
compounds
pharmacokinetic
filters (ADME)
drug-like
compounds
nondrugs
promiscuous compounds,
coloured or fluorescent
molecules
frequent-hitter
detection
drug
candidates
Drug-like characteristics
Lipinski, C. A. et al. Experimental and computational approaches to estimate solubility and permeability in
drug discovery and developmental settings. Advanced Drug Deliv. Rev. 1997, 23, 3-29.
100 nm
McGovern SL, Caselli E, Grigorieff N, Shoichet BK: A common mechanism underlying promiscuous inhibitors
from virtual and high-throughput screening. J Med Chem 2002, 45:1712-1722.
CORINA
Automatic generation of
three-dimensional atomic
COoRdINAtes
http://www.molecular-networks.com/online_demos/corina_demo.html
http://chem.sis.nlm.nih.gov/chemidplus/
http://drugbank.ca/