Definition of pharmaceutical

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

(target binding place stereoelectronic compatibility)

low toxicity

(selectivity, antitargets: CYP, hERG, P-

glycoprotein...)

bioavailablity

(physico-chemical and pharmacological

properties ensuring drug-likeness)

Three mainphases
ofdrug action

pharmaceuticalphase

(biopharmaceutical)

release ofdrug from thedrug form

pharmacokineticphase

(what makesthe

bodywith the drug)

ADME

pharmacodynamicphase

(what makes

thedrugwith the organism)

characterand quality ofdrug

interactions
with
interactionsiteof the biological system

Basic terms in pharmaceutical

chemistry

TARGET (biomacromolecule to interfere with)

BINDING POCKET ACTIVE SITE
(part of the target appropriate to bind a small ligand)
PHARMACOPHORE (a part of a molecule that is recognized at a
receptor site and is responsible for that molecule's biological activity)
LIGAND organic molecule possessing target affinity, that has to be
stereo-electronically compatible with binding pocket
ACTIVE is a compound detected by usually HTS
HIT is a active compound identified in a screen with confirmed
structure and activity, that need to be developed into lead
compound
LEAD is a active compound with convenient properties: druglikeness, solubility, synthetic feasibility, patentability
DRUG CANDIDATE high activity, good selectivity, in vivo efficiency
DRUG after success in clinical trials approved by FDA, EMEA
DRUG-LIKENESS complex properties
(ADME/Tox: Absorption/Distribution/Metabolism/Excretion/Toxicity)

Drug development basic

chronology
selection of disease
cancer )

(cardiovascular, autoimmune, infectious, hereditary, mental,

molecular mechanism of the pathology

(medicine, molecular biology)

selection of a key biomolecule to influence

new active structure/compound identification: in Silico
design, HTS,
of organic molecules possessing appropriate drug-like properties
(biologists, computer chemists)

organic synthesis

(chemists)

biological or biophysical assays

(biologists)

optimization of activity and other molecular properties

IP protection + clinical trials + up-scale synthesis + approval

Pharmaceutical chemistry includes:

The process of discovery =identificationand
production of newactive compounds
natural resources
synthesis
biotechnology
design- computer aided drug design (CADD)

The optimization process

syntheticmodification of theleadsceleton
(structures) to improve
theeffect ,selectivityand suppress toxicity
(S.A.R.)

The development process

optimization ofsyntheticprocessesformass
productionof the drug
modificationof pharmacokinetic propertiesof
the drug(suitable forclinical use)

From were to get active

compounds?
A) The Natural World

B) The Synthetic World

C) The Virtual World

Micro-organisms (bacteria, fungi)

Marine chemistry (corals, bacteria,
fish etc)
Plant life (flowers, trees, bushes)
Animal life (frogs, snakes, scorpions)
Biochemicals (neurotransmitters,
hormones)
Pure natural products, bioextracts
(e.g. plant, or microbial)
Ethnopharmacology (Chinese
LMW
synthetic
compounds
traditional
medicine...)
(traditional, combinatorial synthesis,
historical corporate chemical collections,
commercial sources)
Computer aided drug design (CADD)

to call them active compounds evaluation through biological

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

primary task of the medical chemist is to identify leading sceleton and

its subsequent modification in order to obtain a suitable candidate to
drug that may be introduced into clinical practice
leading structure may have some deficiencies, chemical and biological
characteristics: a lack of specificity, low activity, metabolic, chemical
instability, high toxicity, low bioavailability, poor solubility
irrational approach: make all the easy and available variations of the
leading sceleton
rational process: methods and approaches that describe the
relationship between drug structure and its activity
- knowledge of the spatial (3D) structure of the receptors at atomic
level resolution)
- knowledge of the conformation of ligands and their interaction with
target macromolecules
9

Strategies of modification existing

structures
by chemical modificationwill be
prepared new compounds, whichwill
havehigher activity,lower
toxicity,or better dosage form

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

Are of similar size, shape and valence electron configuration

Classical isosters that can serve as bioisosters:

monovalent atoms and groups
A: CH3 NH2 OH F Cl

bivalent atoms and groups

A: CH2 NH O S Se

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;

B: COCH2 CONH COO

COS
trivalent tetravalent
A: CH= N=
A: >C<
>Si<
B: P= As=B: =C= =N+=
=P+=
12

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

Nonclassical bioisosters of Carboxyl group

COOH

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

Nonclassical bioisosters of Hydroxyl group

R

NOMe

CONMe R R

Nonclassical bioisosters of Amide group

R

OH

Nonclassical bioisosters of Ester group

R

O HC
3

OH

NHCONH2 R

NHCN R

CH(CN)2

Nonclassical bioisosters of Catechol group

HO

HO

N
H

HO

O
X
X = O, NR

HO

Nonclassical bioisosters of Halogen

Halogen

CF3

CN

NCN2

C(CN)3

Nonclassical bioisosters of Urea-like

NHC(=S)NH2

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

The use of biological

information
monitor the effects of random compounds for
new discoveries about biological processes
taking place in biology and medicine
observation of people - folk medicine (Digitalis,
opiates, quinine, atropine, cocaine)
observations in animals - in vivo pharmacological
tests on animals (Vinca rosea - vincristine,
vinblastine)

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

Computational pharmaceutical chemistry

Main object of study
drugs
biological systems associated with drugs (proteins,
enzymes, receptors...)

19

Drug design and

development
Drug-like molecule
Necessary condition
biological activity = f (3D structure +
physicochemical properties)

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

semi-empirical methods (MNDO, AM1, PM3, ...)

Electronic structure
methods

programs: MOPAC, HyperChem, Gaussian, ...

ab initio methods
Hartree-Fock methods
electronic correlation methods
Moller-Plesset Pertubation Theory (MP2, MP3, MP4, MP5)

Density functional methods

B3LYP, B3P86, BLYP, ...

Hybrid methods
ONIOM, QM/MM approaches
Programs: Gaussian, Jaguar,...

Use of these methods:

Geometry and energy calculations
in gas phase
solvent effect

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

CADD is the science and art of finding molecules of potential

therapeutic value that satisfy a whole range of quantitative criteria
such as high potency, high specificity, minimal toxic effect and good
bioavailabity
CADD relies on computers, information science, statistics,
mathematics, physics, biology and medicine
CADD implies the use of computer graphics to visualize and
manipulate chemical structures, to synthesize in silico new
molecules, to determine their conformation, and to assess the
similarities aind dissimilarities between series of molecules
CADD also involves the calculation of the interaction energy between
drug molecules and hypothetical or experimentally determined
macromoleculas structures
24

Computer assisted drug

design
AIM:
to discover, enhance, study biologically active
molecules that will bind to a selected target and if so
how strongly before a compound
is synthesized
to estimate drug-like properties and use them for
elimination of undesirable structures
it still takes several iterations of design, synthesis,
and testing before an optimal molecule is
discovered

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

Rational methods in drug

design
Structure-based drug design
SBDD
Ligand-based drug design LBDD
Fragment-based drug design
FBDD

Structure Based Drug Design SBDD

relies on knowledge of the 3D structure of the
biological target obtained through X-ray
crystallography or NMR spectroscopy
SBDD be divided roughly into two categories
finding ligands for a given receptor (database searching).
A large number of potential ligand molecules are screened to find
those fitting the binding pocket of the receptor. It saves
synthetic effort to obtain new active compounds.

building ligands (receptor-based drug design). In this case,

ligand molecules are built up within the constraints of the
binding pocket by assembling small pieces (atoms,
fragments) in a stepwise manner. The key advantage is that
novel structures, not contained in any database, can be
suggested.

Ligand Based Drug Design

LBDD (indirect DD)
relies on knowledge of known molecules that bind to the
biological target (known: structure and bioactivity IC 50)

These molecules (ligands) may be used to derive a pharmacophore

model which defines the minimum necessary structural
characteristics a molecule must possess in order to bind to the target.

Virtual screening (based on pharmacophore models; high-throughput

docking) including drug property filtering (Zinc database)

Alternatively, a quantitative structure-activity relationship (QSAR) in

which a correlation between calculated properties of molecules
and their experimentally determined biological activity may be
derived. These may be used to predict the activity of new
analogues.

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

EGFR inhibitor gefinitib (IRRESA)

(approved for refractory lung cancer, AstraZeneca)
EGFR (ErbB, HER1) tyrosine kinase receptor: abnormal or over-expressed in the breast, lung,
brain, prostate, gastrointestinal tract, ovaries cancer. EGFR is a receptor for EGF proteins (1986
Nobel Prize). Upon activation by its growth factor, EGFR forms active homodimer possessing
intracellular TK activity that initiate several signal transduction cascades leading to DNA
synthesis and cell proliferation. Gefitinib inhibits EGFR by binding to the ATP-binding site.
Thus receptor and therefore also malignant cells are inhibited.

4-anilinoquinazoline SAR optimized

Lead I, good in vitro activity, in vivo
hampered by rapid metabolism
caused by cytochrome P450
enzymes

main metabolic products I, II

both met. routes

blocked

Cl- similar in size and lipophilicity as Me- group

F- almost the same size as H- (no steric effect)
both groups are resistant to oxidation, better in vivo
activity, pharmacokinetic properties improved by
morpholino group, because of basic nitrogen that
enhanced water solubility

What should compound fulfill to become

a drug?
Biol. active, chemically stable compound possessing
appropriate:
pharmacodynamic properties (activity, selectivity)
pharmacokinetic properties (bioavailability: ADME/TOX)
others (novelty, scale up synthesis...)

> 30% of all drug failures can be attributed to poor

physiochemical properties: Log P (Log D), pKa, and solubility
all have impacts on drug absorption and diffusion in vivo
Chemical Space

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's Rule of Five (Ro5)

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)

Sum of hydrogen bond donors 5 (NH,OH)

Sum of hydrogen bond acceptors 10 (N,O)
C. A. Lipinski et al. Adv. Drug Del. Rev. 1997, 23, 3. (Ro5)
Greg M. Pearl et al., Mol. Pharmaceutics, 2007, 4, 556560. (log D introduced)

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)

PSA < 140 2(Molecular Polar Surface Area sum of

surfaces of polar atoms (N,O...with H) that correlates with

human intestinal and BBB absorption) for good BBB penetration
(PSA < 60 2)

Number of rotatable bonds < 10

(flexibility factor)
(high NRB many conformers)

Ertl, P. in Molecular Drug Properties, R. Mannhold (ed), Wiley-VCH , 2007, 111 126.

Ro5 determined from 2D

tructure
http://www.molinspiration.com

Ertl, P. et al., J. Med. Chem. 2000, 43: 3714-3717. (molecular property prediction toolkit )

Ro5 violations

Absorption as f(PSA, LogP)

logP

(membrane transport connected with fat and water

solubility)

log pKa

(influences binding Ki and also logP)

Intestinal and other absorption

% ABS = 109 0.345 PSA (good when %ABS > 30 %)

(lower PSA, higher absorption)

Zao YH et al. Pharm Res 2002, 19, 1446-1457.

Brain Blood Barrier penetration

LogBB = -0.0148 PSA + 0.152 CLogP + 0.139
(to estimate CNS penetration and possible side effects)
BB = C-brain / C-blood
CNS:
logBB > -0.5 (side effects)
non CNS:
logBB < -1

Other considerations
despite good druglikeness some compounds
should be avoided as drug candidates:

If contain substructures with known reactive, toxic,

mutagenic or teratogenic properties (RCOX, (RCO)2O,
Michael acceptors, epoxides, -NO2, -NO, -N3, NH-NH, N=N...)

bad metabolic parameters, e.g. fast metabolism can

quickly destroy the pharmacological activity of the
compound (metabolic half life, metabolic clearance should be
determined)

Inhibit antimetabolites (CYP, hERG, P-glycoprotein)