Disseny de Fàrmacs

Pràctica

Dr Carles Galdeano
cgaldeano@ub.edu

Sec. Depart. Fisicoquímica

Facultat de Farmacia I Ciencie de l’Alimentació
•An important part ofcomputational drug design is the prediction of small
molecules binding to a target protein.

(Molecular recognition)

BINDING VS ACTIVITY

DGbind
Molecular RecogniOon
Molecular
Basic RecogniOon
Principles
Basic Principles

• Ligand-Receptor recognition is high

• Ligand-Receptor recognition is highly
selective & specific
selective & specific
Highaffinity
• •• High affinity
Geometry alone
cancan only be achieved
is insufficient
only to
be achieved
through
recognise
through excellent
the correct
excellent complementarity:
ligand
complementarity:
Electrostatics
• • Electrostatics (ionic,
(ionic, H-bonds)
H-bonds)
• The•binding
Steric
site-ligand match is
• Steric
based on: geometry and
Hydrophobic
• • Hydrophobic
electrostatics
• Geometric and electrostatic
complementarity can be achieved
using different BS architectures
Given that the rules of molecular recognition
Given that the rules of molecular recognitio
are understood, qualitative assessment of
are understood, qualitative assessment of
ΔΔGbind can be obtained from visual inspection
ofΔΔG bind canorbe
complexes obtained from
approximate visual
scoring inspectio
functions
of complexes or approximate scoring functio
Molecular RecogniOon
Molecular
Basic RecogniOon
Principles
Basic Principles

• Ligand-Receptor recognition is high

• Ligand-Receptor recognition is highly
selective & specific
selective & specific
Highaffinity
• • High affinity can
can only
only be achieved
be achieved
through
through excellent
excellent complementarity:
complementarity:
Electrostatics
• • Electrostatics (ionic,
(ionic, H-bonds)
H-bonds)
Steric
• • Steric
Hydrophobic
• • Hydrophobic

Given that the rules of molecular recognition

Given that the rules of molecular recognitio
are understood, qualitative assessment of
are understood, qualitative assessment of
ΔΔGbind can be obtained from visual inspection
ofΔΔG bind canorbe
complexes obtained from
approximate visual
scoring inspectio
functions
of complexes or approximate scoring functio
 Molecular Recognition
Enthalpic and entropic components of binding

Adapted from GE
 Molecular Recognition
Enthalpic and entropic components of binding

Adapted from GE
 Molecular Recognition
Enthalpic and entropic components of binding

Adapted from GE
Molecular Recognition
Cooperativity
 e rs lity
at ib i
l w lex
ura d f
r uct gan
S t /li
• ility
x ib tion
fle lva
te in
D e so
Pro •
•
 . Protein flexibility

nding Site Flexibility

HSP90 example
(1BYQ vs. 1UY6)

VISUALIZATION:
. Structural waters

Interstitial & displaceable water molecules

• Remaining water molecules must form a Ody

network of interacOons
• Intrinsic preferences + ligand-specific effects
Specific'Intramolecular'interac1ons'
• Hydrogen'bonds'
Figure 8. Radial distribution of hydrogen atoms around a phenyl ring (CSD st
5066 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 14 two heteroatoms (N, O); (b) hydrogen bound to O or N. Queries
Bissantz et al. were set up as

more
• Distance:*2.7*–*3.5*A'
drawn roughly to scale and should serve as an interpretation aid for the in-plane
higherhydrogen
density; peaks
bonds above
can abenumerical
formed.value of 70 are
Analyses colored red.
of entire
protein structures showed that both NH and CO groups form
hydrogen bonds to a very large percentage,88 in particular in dono
high resolution crystal structures, and the remaining cases can tions
usually be explained by artifacts of the crystal structures hydr
or inadequacies of the search methods.89 The number of show
observed hydrogen bonds clearly increases with decreasing
nors.
solvent accessibility.90 There is evidence, however, that not
satisfying a hydrogen bond donor in a protein, i.e., burying a a thr
donor in a desolvated state, has more drastic energetic con- fluor
sequences than not satisfying an acceptor. Homas et al. report catio
a penalty of 4.3-5.3 kcal/mol for a hydroxyl group binding in regar
91
a hydrophobic pocket, due to the cost of desolvation. the c
Relatively little loss of free energy is incurred upon removal subst
of a hydrogen bond to a backbone carbonyl group. Bartlett dines

'
and co-workers showed that replacements of NH by a methy- Ha
lene group hardly reduced the binding affinity of peptidomi- publ
metic thermolysin inhibitors, whereas the replacement of NH
• Angular'preferences'
halog
Figure
by 9. Box
oxygen plotsa of
allowed hydrogen
dramatic lossbond lengthby
in affinity 4 kcal/mol.92
distributions for the
tions
interaction
The bindingbetween weak tripeptides
of acylated and strong and donors
theirand amide carbonyl
analogues to
oxygen as acceptor The
vancomycin gives (CSD statistics).
a similar picture:Anreplacement
increase in median
of NHhydrogen
by
bond length
methylene andtoina breadth
leads loss of 1.5of kcal
the distribution
in binding freeis observed
energy, for norm
decreasing donor strength. 93 behin
• Weak'Hydrogen'bonds' halog
replacement by oxygen to a loss of 4.1 kcal/mol. In a series of
Chk1 inhibitors,
124
a reduction in binding affinity of 1.4 kcal/mol
Figure 5. Schematic depiction of the most preferred geometries of bonds.
was observedWeinhave observed
changing a thrombin
follo
a pyrrole inhibitor
to a furane to change
ring where in
hydrogen bond interactions with various types of acceptors: (a) pyri-
dine nitrogen, (b) carbonyl oxygen, (c) carboxylic acid, (d) ether
oxygen, (e) sulfonyl group.
its binding
both cases the
'
mode
a CF 3 3 3 group.
carbonyl
upon fluorination
heteroatoms
HN interaction
inter
point toward
is formed.
As in the previous In
ofthe
125
anCys87
aryl ring,
two examples,
such that
backbone
In another study
this loss of on

distance of 2.79 Å. With a neutral amine as a counterpart, this

affinity
factor VIIa
repulsive
to act as O '
is probably mostly
inhibitors,
3 O interaction
an3 3isostere
due to thephenyl
a fluorinated
elect
of a pyridine.
draw
94
introduction
ring was
126 due to the removal
rather than An increase
of shown
of
a
affinity
distance increases to 2.83 Å. A hydrogen bond between amide of the NH
from 3 3 O68hydrogen
455 3 to nM wasbond.observed in sitagliptin analogues dens
Specific'Intramolecular'interac1ons'
• π'–'stacking'
'''''''''>'Between'Aroma1c'rings'

Distances:*****************************3.623.8*A************3.423.6*A*
Specific'Intramolecular'interac1ons'
• Ionic'bond'(interac1on'with'Glu,'Asp,'Lys,'Arg)'
• Halogen'bonds'(F,'Cl,'Br,'I)'
'''''''>'weaker'than'hydrogen'bonds'
'''>'Sigma'hole'of'halogens'
'''2*Distance*3.0*23.5*A*
''
• Halogens'and'aroma1c'rings'
' ' ' 'Distance*3.32*4.4*A*
• Dipole>dipole'
• Hydrophobic'interac1ons'(van'der'Waals)'
 Bioinformàtica
Pràctica reconeixement molecular
Dr Carles Galdeano
cgaldeano@ub.edu

Sec. Depart. Fisicoquímica

Facultat de Farmacia I Ciencie de l’Alimentació