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chemistry
pharmaceutical chemistry
discovery
development
identificationand interpretation ofthe mode of
actionof biologically active compoundsat the
molecular level
pharmaceutical chemistry is an
interdisciplinary science
pharmacology, biochemistry, molecular biology,
imunology
(life sciences)
organic, physical, theoretical chemistry, molecular
spectroscopy, crystallography, (chemical sciences)
information technology
Drugs
Organic
(inorganic)
compounds
and
biomolecules (proteins, antibodies, ) that activates or
inhibits the function of a target with benefit to the
patient
activity
low toxicity
glycoprotein...)
bioavailablity
Three mainphases
ofdrug action
pharmaceuticalphase
(biopharmaceutical)
pharmacokineticphase
(what makesthe
ADME
pharmacodynamicphase
(what makes
organic synthesis
(chemists)
(biologists)
Pharmaceutical research
and development (R & D)
discoveryof a newlead sceleton is a keystep
inanyresearch program
nowdays it is also themost problematic stage of
development ofa newdrug
Discoveryof new lead structures in70s20th century
-random selection (randomobservation,a
happydiscovery, screeninga large number ofcompounds)
Nowdays:racional procedures
based on theknowledgestructureof endogenous
metabolites,enzymes, receptors and the nature ofthe
biochemicaldefect that caused thedisease
Structure activity
relationship
10
Bioisosteric substitution
is based on the knowledge that
certain physical properties of
chemically different compounds are
strikingly similar
bioisosters are considered a group of
compounds which have the chemical
and physical properties that produce
similar biological effect
11
Classical bioisosters
B: Cl PH2 SH
C: Br i-Pr
D: I t-Bu
ring equivalents
A: CH=CH S (benzene;
tiophene)
B: CH= N=
(benzene;
pyridine)
C: O S CH2 NH
(tetrahydrofurane;
Nonclassical bioisosters
Nonclassical bioisosters of Carbonyl group
R
Are of different
number of atoms,
do not meet the
steric and electron
rules of classical
bioisosters, but
evoke similar
biological activity
CN
O
R
S
R
CN
CN
R O
SO2
HC
SO 2NHR
CONHCN
CONHOH
PO(OH)OEt
PO(OH)NH2
SO3H
O
COO
R
N
R R
O
CONH R R
CSNH
RR
CH2NH R C
R
OH R
NHCOR R
NHSO 2R R
CH2OH R
CH2S R
NOMe
CONMe R R
OH
O HC
3
OH
NHCONH2 R
NHCN R
CH(CN)2
HO
N
H
HO
O
X
X = O, NR
HO
CF3
CN
NCN2
C(CN)3
NHC(=NCN)NH2
NHC(=CHNO2)NH2
13
Systematic screening
systematic testing of new compounds
without the known mechanism of action and
pharmacological potential
extensive screening - a comprehensive
pharmacological assessment is subjected to
a limited number of advanced structures
random screening - from large number of
compounds (hundreds-thousands) is looking
for one which is active in the indication
14
15
Rational drug
development
rational design consist of the
knowledge of the molecular level of
the disease
16
Genetics, genomics
and drug development
Over the last 15 to 25 years there has been progress
in several scientific fields, particularly combinatorial
chemistry, genomics, proteomics and bioinformatics,
which are promise for the future in a streamlining of
procedures discovering new drugs.
The main idea of new methods of research and drug
development is to identify the biological action, gene
or protein that is disrupted in the disease process.
Then, on the basis of this knowledge could be design
a drug that specifically interact with the site of
action
17
Computational
pharmaceutical chemistry
18
Computational
pharmaceutical chemistry
Computational chemistry
is a discipline using mathematical methods for the
calculation (computer-assisted) of molecular
properties or for the simulation of molecular
behaviour
most used methods
quantum mechanics
classical mechanics
19
Sufficient condition
high-affinity ligand must exhibit also good
pharmacokinetic and toxicological properties
pharmacokinetic ADMET (Absorption, Distribution,
Metabolism, Excretion and toxicity ) parameters
(poor biopharmaceutical properties and toxicity are one
of the major reason for drug development failure)
20
Molecular modeling
and
medicinal chemistry
Molecular modeling methods
Quantum chemistry
Molecular Mechanics
Molecular Dynamics and Monte Carlo
21
Electronic structure
methods
ab initio methods
Hartree-Fock methods
electronic correlation methods
Moller-Plesset Pertubation Theory (MP2, MP3, MP4, MP5)
Hybrid methods
ONIOM, QM/MM approaches
Programs: Gaussian, Jaguar,...
22
Computer-Assisted Drug
Design
CADD (Computer-Assisted Drug Design)
was developed by applying methods and
theories of computational chemistry to
study the properties of drugs
can be applied to any active molecules,
which interact with the receptor is known
23
Computer-assisted drug
design (CADD)
Computer-assisted drug design
involves all computer-assisted techniques used to discover, design and
optimize biologically active compounds with a putative use as drugs
Target
selection
Do we
know 3D
structure
of
homolog
protein?
Do we
know
3D
structu
re?
New
lead
compou
nd
Databas
e
searchin
g
Molecula
r
docking
SBDD
LBDD
What
compoun
d?
What
compoun
d?
New
lead
compou
nd
Databas
e
searchin
g
Optimize
d
structure
Design
de novo
Fragmen
t docking
Active
analog
model
Pharmacoph
ore model
Optimize
d
structure
Design
de novo
QSAR
model
26
design
Structure-based drug design
SBDD
Ligand-based drug design LBDD
Fragment-based drug design
FBDD
Pharmacophore
spatial (3D) arrangement of
functional groups of ligand molecules
that react with the active site of the
receptor
actually defines "natural" dimensions
of the ligand molecule
30
Lead-like
Chem Space: 10 - 10
DB of 11 atoms C,N,O, F: 26 400 000 stable
compounds (110.9 M if stereoisomers included)
J.-L. Reimond J. Chem. Inf. Model. 47, 2007, 342.
60
200
Drug-like
Drugs
Bioavailability
(in vitro) active compound, to perform as drug, has to
reach its target in the human body (in vivo)
Drug-likeness is qualitative concept to estimate
bioavailability from the molecular structure before the
substance is synthesized. The drug-like molecule has to
have:
optimal MW and number of HBD, HBA (affecting solubility and
absorption)
optimal water and fat solubility logP (octanol / water) (intestinal
lining, aqueous blood, penetrate cellular membrane to rich inside the
cell) The distribution coefficient (Log D) is the correct descriptor for
ionisable systems. log D is pH dependent (e.g. at pH = 7.4 is the
physiological pH of blood serum)
Lipinski Ro5
(all numbers are multiples of five, empiric
rule)
for prediction of bioavailability (not activity!) to
quickly
eliminate compounds that have poor physicochemical
properties for oral bioavailabilty
an orally active drug has no more than one violation
of the following criteria:
MW 500
Lipophilicity (logP 5) octanol-water partition
coefficient (better log D 5 respecting the ionic states
present at physiological pH values)
Additional drug-like
parameters
MW 500
Lipophilicity (logP 5) octanol-water partition
coefficient
Sum of hydrogen bond donors 5 (NH,OH)
Sum of hydrogen bond acceptors 10 (N,O)
Ertl, P. in Molecular Drug Properties, R. Mannhold (ed), Wiley-VCH , 2007, 111 126.
tructure
http://www.molinspiration.com
Ertl, P. et al., J. Med. Chem. 2000, 43: 3714-3717. (molecular property prediction toolkit )
Ro5 violations
logP
log pKa
Other considerations
despite good druglikeness some compounds
should be avoided as drug candidates: