M O L E C U L A R P R I N C I P L E S O F D R U G D E S I G N
M G R . A N N A H U D C O V Á
D E P A R T M E N T O F C H E M I C A L D R U G S
U V P S B R N O
CHEMOGENOMICS
AND
THEORY OF PRIVILEGED
STRUCTURES
CHEMOGENOMICS
aims towards
the systematic identification
of small molecules
that interact with the products of
genome and
modulate their biological function
CHEMOGENOMICS
=
the discovery and description of
all possible drugs
for
all possible drug targets
Some definitions
 GENOMICS = an interdisciplinary field of science focusing on
the structure, function, evolution, mapping, and editing of
genome
 Genome = a genome is an organism's complete set of DNA,
including all of its genes
 Human Genome Project (1990-2003): identification of 20000-25000
genes in human DNA
 Genetics = study of individual genes and their role in
inheritance
 PROTEOMICS = refers to the large-scale experimental
analysis of protein
 Proteome = the entire set of proteins that are produced or
modified by an organism or systhem
More definitions
 Chemical genomics / CHEMOGENOMICS
 the systematic identification of small molecules that interact via a
specific molecular recognition mode with target proteins encoded by
the genome
 the term chemogenomics is applied more specifically to target family
approaches in drug discovery
 Chemical genetics
 identify chemical compounds which induce or revert specific
biological phenotypes by using cell-based or microorganism-based
screening of compound
 Chemical biology
 the functional and mechanistic investigation of biological systems
using chemical compounds and constitutes a more general discipline
The chemogenomic terminology
 1996
 Glaco Wellcome
 Systematization of drug discovery within target
families based on the analysis of gene families
Traditional approach
 Based on therapeutic areas
 Genomically unrelated targets are addressed
together
 Example: therapy of neurodegenerative diseases
 Acetylcholine and their derivarives
 Antagonists of muscarinic and nicotinic receptors (target =
receptor)
 Inhibitors of acetylcholinesterase (target = enzyme)
 Inhibitors of β-amyloid agregation (target = protein)
Chemogenomic approach
 Analysis does not depend on knowledge of biological
function
 Members of the same protein family can share
important practical aspects
 Similar ligands should bind to similar target →
knowledge previously obtained → transferable to
new related projects
How?
I. identification of all members of a gene
family
II. classification into subfamilies
III. revelation of common elements and
patterns in the sequence and tertiary
structures
Classification of proteins
 Conventional phylogenetic
WHOLE STRUCTURE
 Chemogenomic
SMALL-MOLECULE BINDING SITES
(only part of enzyme structure, most commonly in
active site of the enzyme)
Example
CHEMOGENOMIC APPROACH
IN CARDIOVASCULAR DISEASES
1. identification of target structures associated with
cardiovascular diseases (literature research)
2. organisation of cardiovascular targets in protein
families
 target families: GPCR (G-related couple proteins), enzyme,
kinase, proteinase, nuclear receptor, catalytic receptor, ion
channel, transporter, other protein
Example
3. the establishment of knowledge base of the
cardiovascular target space
 determining the level of applicability of structurebased
methods for in silico target profiling
 is the structure of targets known?
 if it is – is there any relationship, similarity?
4. using only known structures
 which belong to Homo sapiens?
Example
5. data from chemical libraries
 ligands with pharmacological potency at (at least
one of) cardiovascular target structure
6. identification of atomic frameworks or
scaffolds
7. synthesis
8. testing on cells
PRIVILEGED STRUCTURES
Privileged structure is
a single molecular framework
able to provide ligands
for diverse receptors.
Evans and co-workers, 1988
Why are so interesting?
 New drug targets
 Bring a new drug to market
 Modeling of potential “small molecules”
 number of possible small molecules is 10E200
 drug-like properties may have 10E60
Characteristics
 constitute a significant portion of the total mass of
the molecule
 represent the core element of the molecule
 physico-chemical characteristics for promiscuous
binding
 smaller molecule has higher capacity of binding to
multiple receptors
 simple ligand surface
Characteristics 2
Cyclic structures are ideal scaffolds for drug
development
 molecular rigidity
 better bioavailability
 bicyclic and tricyclic molecules are ideal size for
library synthesis
Characteristics 3
Promiscuous ligands:
 potently
 specifically
 reversibly
 but not selectively
bind to members of different macromolecular target
families
Limites?
 Have they limited utility due to their promiscuous
nature?
 Ex. Biphenyl framework has been described as a
preferred substructure for protein binding – appears in
4,3% of all known drugs
 This may indicate that although privileged substructures
have the capacity to bind nonspecifically to a number of
receptors, THE SUBSTITUENTS attached to the scaffold
may be responsible for its receptor specificity, while the
scaffold itself provides a number of features conductive
to binding
1. Library based upon one core scaffold
 Screen against a variety of different receptors
 Example on 1,4-benzodiazepin-2-ones
 Small library of 192 molecules => cholecystokinin A receptor =>
several active compounds => larger library of 1680 compounds
 Possible explanation?
 Targets
 Cholecystokinin (devazepine)
 Gastrin
 Central benzodiazepine receptors (lorazepam)
 Neurokinin-1 antagonistS
 K-secretase inhibitors
 Farnesyl:protein transferase inhibitors
 Delayed rectifier K+ current modulator
2. DOS
 Diversity Oriented Synthesis
 Novel drug-likecompounds with a high degree of
molecular diversity
 Resulting DOS-derived libraries contain complex
and diverse structures with a high fraction of sp3hybridized
carbon atoms and more stereogenic
centers
3. pDOS
 Privileged-substructure-based Diversity
Oriented Synthesis
 privileged substructures from natural products as
chemical navigators
 polyheterocycles – example benzopyranyl motif
was identified in biological evaluations:
 a nonsteroidal androgen receptor antagonist
 a small-molecule modulator with insulin-independent
antidiabetic and antiobesity effects
 a small-molecule anabolic activator of osteogenetic activity
4. Combinatorial chemistry
 Comprises chemical synthetic methods that make it
possible to prepare a large number (tens to thousands or
even millions) of compounds in a single process.
 High-Throughput Screening (HTS)
 method for biological testing large chemical libraries
 using robotics, data processing/control software, liquid handling
devices, and sensitive detectors, high-throughput screening allows a
researcher to quickly conduct millions of chemical, genetic, or
pharmacological test
 the microtiter plate: a small container, usually disposable and made
of plastic, that features a grid of small, open divots called wells
(multiples of 96)
5. BIOS
 Biology Oriented Synthesis
 use of core structures derived from bioactive natural
products as synthetic scaffolds
 structural motif and core skeletons from bioactive
natural products can serve as chemical “navigators”
for the synthesis of novel core skeletons
6. CtD
 Complexity-to-Diversity strategy
 construction of natural product-like small-molecule
collections starting from commercially available
natural products (abietic acid, adrenosterone,
quinine)
Organic scaffolds as privileged structures
 1,4-benzodiazepin-2-one
 biphenyl
 1,4-dihydropyridine
 benzopyran
 pyranocoumarin
 2,6-dichloro-9-thiabicyclo[3.3.1]nonane
 isoxazole
 3,5-linked pyrrolin-4-ones
 β-glucose
 monosacharides in general
 benzazepinone
 diphenylmethane
 biphenyltetrazole
 spiropiperidine
 4-substituted piperidine
 indole
 benzylpiperidine
 phenylpiperazine
THANK YOU