drug design steps.pdf
DESCRIPTION
A short description for students of the Drug Design steps and approachesTRANSCRIPT
Drug Design - A multiple task
Drug design may be approached in various ways, but basic concepts
about drugs, receptors, and drug–receptor interactions are of highest
importance.
Conceiving drug design may be divided into three logical steps:
���� Step 1-The drug: Know what properties turn a synthesized
molecule into a drug.
Step 2-The drug receptor: Know what properties turn a
molecule into a drug.
���� Step 2-The drug receptor: Know what properties turn a
macromolecule from the human body into a drug receptor
���� Step 3-The fitness: Know how to design and synthesize the drug
in order to fit into a receptor
The process of drug design must be validated by actually making and
testing the drug molecule. An ideal synthesis should be simple, be
efficient, and produce the drug in high yield and high purity.
����Step 1
involves knowing WHAT PROPERTIES TURN A MOLECULE INTO A DRUGWHAT PROPERTIES TURN A MOLECULE INTO A DRUG.
[intermediately a drug-like molecule (DLM)]
Drug molecules
� are “small” organic molecules (molecular weight usually below
800 g/mol, often below 500);
� should present certain properties (geometric, conformational,
stereochemical, electronic) appropriate to make it a drug-like molecule stereochemical, electronic) appropriate to make it a drug-like molecule
(DLM).
� are complex and have sub-unit parts (biophores) in order to:
� interact with the receptor(s) (go to Step 2),
� permit the body to absorb, distribute, metabolize, and
excrete (A-D-M-E) the drug molecule.
When designing a molecule, a design tool is used, such as Computer-
aided molecular design (CAMD), which incorporates molecular
mechanics and quantum mechanics.
����Step 2
involves knowing WHAT PROPERTIES TURN A MACROMOLECULE FROM WHAT PROPERTIES TURN A MACROMOLECULE FROM
THE BODY INTO A RECEPTORTHE BODY INTO A RECEPTOR.
Receptor macromolecules
� are frequently proteins or glycoproteins or parts of them as
fluid, flexible surfaces or pockets
� most receptors are already sites for natural ligands� most receptors are already sites for natural ligands
� should present certain properties appropriate in order to make
them druggable target(s).
� should be intimately connected with the disease in question
Step 3
involves CONNECTING A DRUG–RECEPTOR INTERACTION TO A HUMAN DISEASE
DESIGNING A SPECIFIC DRUG-LIKE MOLECULE TO FIT INTO A PARTICULAR
DRUGGABLE TARGET.
This phase of drug design requires the understanding of biochemistry and of
the molecular pathology of the disease being treated.
This phase of drug development, which connects the drug–receptor
interaction to human disease, is based on three logical approaches (that interaction to human disease, is based on three logical approaches (that
mark the three main drug targets):
����Aproach A. Know how to manipulate the body’s endogenous control
systems
����Approach B. Know how to manipulate the body’s endogenous
macromolecules.
����Approach C. Know how to inactivate a harmful exogenous agent
The prototype compound (the lead compound) is then optimized by QSAR
studies and finally validated by synthesis and tests.
How drug act ?
Paul Ehrlich :
“Corpora non agunt nisi fixata”, i.e. A drug will not work
unless it is bound
The traditional model for Receptors was a The traditional model for Receptors was a
rigid “Lock and Key”
– Lock � Receptor surface
– Key � Drug or Ligand
– Receptor can change 3-D structure as
ligand docksReceptor
Drug
The therapeutic goal is to bring back the human body to its normal
balanced, harmonious state, called homeostasis. The approaches to
attaining this govern also one of the drugs’ classification:
A. To know the body’s normal inner (endogenous) control systems for
maintaining homeostasis through day-to-day or minute-to-minute
adjustments. These control systems (for example, neurotransmitters,
hormones, immunomodulators,) are the first line of defense against
perturbations of homeostasis.perturbations of homeostasis.
B. If there are no data on the endogenous control systems, how about
identifying other targets on endogenous cellular structures or
macromolecules?
C. Alternatively, it may be easier to attack the cause of the pathology.
If there is a harmful microorganism or toxin in the environment
(exogenous), then it may be possible to directly attack this exogenous
threat to health and inactivate it.
Approach C.
Both the three steps (Step 1, Step 2, and Step 3, above
mentioned) and the three Approaches (A, B, C) are the
milestones of drug design.
A Drug as a Composite of Molecular Fragments
Drug molecules are conceptualized as being assembled from biologically
active building blocks (biophores) that are covalently “snapped together”
to form an overall molecule.
Thus, a drug molecule is a multiphore, composed of a fragment that
enables it to bind to a receptor (pharmacophore), a fragment that
influences its metabolism in the body (metabophore), and one or more
fragments that may contribute to toxicity (toxicophores).fragments that may contribute to toxicity (toxicophores).
The drug designer should have the ability to optimize the pharmacophore
while minimizing the number of toxicophores. To achieve this design
strategy, these fragments or building blocks may be replaced or
interchanged to modify the drug structure.
Certain building blocks (called bioisosteres), which are biologically
equivalent but not necessarily chemically equivalent, may be used to
promote the optimization of the drug’s biological properties.
A drug molecule possesses one or more functional
groups positioned on a structural framework (e.g. the
hydrocarbonate skeleton, any aromatic rings, any rigid
conformations/configurations, etc) that holds the
functional groups in a defined geometrical array that
enables the molecule to bind specifically to a targeted
biological macromolecule, the receptor.
The general pattern of drug action [D = drug, R = receptor (druggable target)]
Not every area of the receptor is fit for a particular drug binding
The framework upon which the functional groups are displayed is
typically a hydrocarbon structure (e.g., aromatic ring, alkyl chain) and is
usually chemically inert so that it does not participate in the binding
process.
The structural framework should also be relatively rigid
(“conformationally constrained”) to ensure that all of the functional
groups are not flexible in geometry, thus preventing the drug from
interacting with untargeted receptors by altering its molecular shape. interacting with untargeted receptors by altering its molecular shape.
The desired biological response should be beneficial (by inhibiting
pathological processes)
No other binding (if possible) to other untargeted receptors is intended,
thus minimizing the probability of toxicity/side effects.
Also drug-like molecules (DLM) should possess the chemical and physical
properties that will enable it to become a drug molecule if an appropriate
receptor is identified
What are the properties that enable a common molecule to become a
drug–like molecule?
The molecule should be
# small enough to be transported throughout the body,
# hydrophilic enough to dissolve in the blood stream,
# lipophilic enough to cross fat barriers within the body.
# It should contain enough polar groups to enable it to bind to a # It should contain enough polar groups to enable it to bind to a
receptor, but not so many that it would cause to be excreted too
quickly from the body, limiting thus the therapeutic effect.
Lipinski’s Rule of Five does a good job of quantifying these properties.
� a drug-like molecule should have a molecular weight less than 500,
� a logP (logarithm of its octanol–water partition coefficient) value < 5
� < 5 hydrogen bonding donors,
� < 10 hydrogen bonding acceptors.
According to the above mentioned theory of the drug &
receptor relationship, a druggable target should also
posess features to support the model:
Druggable targets R :
are macromolecules
are usually proteins
show biological response
Conclusion:
Certain properties permit a molecule to become a drug-like molecule and
certain properties permit a macromolecule to become a druggable target.
When a drug-like molecule interacts with a druggable target to give a
biological response, the drug-like molecule becomes a drug molecule and
the druggable target becomes a receptor.
show biological response
Biophores ─ Structural Fragments of a Drug Molecule:
Pharmacophore, Toxicophore, Metabophore
Pharmacophore
The three-dimensional arrangement of atoms within a drug molecule that
permits a specific binding interaction with a desired receptor is called the
pharmacophore. This is the bioactive face of the drug
The molecular baggage: the Toxicophore & Metabophore
The other portions of the drug molecule that are not part of the
pharmacophore constitute the molecular baggage. The role of this
molecular baggage is to hold the functional group atoms of the
pharmacophore in a fixed geometric arrangement (with minimal
conformational flexibility) to permit a specific receptor interaction.
The molecular baggage consists of two other less frequently discussed
fragments of a drug molecule, i.e. the toxicophore and the metabophore.
Conceptually, these two fragments are analogous to the pharmacophore.
Several toxicophores multiple toxicities arising from several
undesirable interactions
if a toxicophore does not overlap with the pharmacophore
The toxicophore
the three-dimensional arrangement of
atoms in a drug molecule that is
responsible for a toxicity-eliciting interaction.
if a toxicophore does not overlap with the pharmacophore
in a given drug molecule, then it may be possible to redesign the
molecule to eliminate the toxicity.
if the pharmacophore and toxicophore
are congruent molecular fragments, then the
toxicity is inseparable from the desired
pharmacological properties.
The metabophore
responsible for the metabolic properties.
Since functional groups are responsible not only for drug–
receptor interactions but also for metabolic properties, the receptor interactions but also for metabolic properties, the
metabophore and the pharmacophore tend to be inextricably
overlapped.
Nevertheless, from the viewpoint of drug design, it is
sometimes possible to manipulate the structure of either the
pharmacophore or the molecular baggage portions of the drug
molecule to achieve a convenient metabophore (e.g. that
either hastens or delays renal excretion).
It is sometimes possible to replace all or part of
the pharmacophore with a biologically equivalent
fragment called a bioisostere.
When designing or constructing a drug molecule,
one can thus pursue a fragment-by-fragment
building block approach.
Certain molecular fragments, although structurally
distinct from each other, may behave identically distinct from each other, may behave identically
within the biological milieu of the receptor
microenvironment.
E.g. replacing the sulphonate (SO42–) with a bioisosterically
equivalent carboxylate (CO32–) group, would bring a prolonged
half-life (the interval within which the concentration of the drug
decreases to half of its initial one) for the drug molecule since
the carboxylate is less polar than the sulphonate and is thus
less susceptible to rapid renal excretion.
Structural Properties of Drug Molecules
In a drug molecule the collection of molecular fragments are held
in a three-dimensional arrangement that determines and defines
all of the properties of the drug molecules.
These properties dictate the therapeutic, toxic, and metabolic
characteristics of the overall drug molecule.
These properties also completely control the ability of the drug to
resist to the chemical changes that may occur from the point of
administration to the receptor site buried deep within the body.
These physical properties of drug molecules may be categorized
into the following major groupings:
1. Physicochemical properties
2. Shape properties
3. Electronic properties
The structural characteristics of a drug molecule (size, shape, topology, polarity,
chirality) that influence its ability to interact with a receptor.
Each of these properties is required for the unique pharmacological activity of a
drug molecule.
1. Physicochemical properties
Physicochemical properties are crucial to the pharmaceutical
and pharmacokinetic phases of drug action determining the
pharmacodynamic interaction of the drug with its receptor.
Physicochemical properties reflect the
solubility and solubility and
absorption characteristics of the drug and
its ability to cross barriers, such as the blood–brain
barrier, on its way to the receptor.
2. Shape properties (stereochemical, geometric, steric, conformational, topological)
describe the structural arrangement of the atoms within the drug
molecule and influence the geometry of approach as the drug
molecule enters the realm of the receptor.
3. Electronic properties
reflect electron distribution within the drug molecule and determine
the nature of the interaction between the drug and its receptor (by
hydrogen bonding and other forms of electrostatic interaction).
From the perspective of the drug designer, they are among the
most difficult to predict and to engineer.
Accordingly, extensive use is now made of quantum mechanics and
classical mechanics force field calculations to determine electronic
and structural properties of drug molecules
Drugs formulation.
A pill is a complicated mixture of non-toxic excipient additives:
Fillers (to ensure that the pill is large enough to be seen and handled;
Fillers include dextrose, lactose, calcium triphosphate, sodium
chloride, and microcrystalline cellulose)
Binders (to permit the pill to be compressed into a tablet; binders
include acacia, ethyl cellulose, gelatin, starch mucilage, glucose
syrup, sodium alginate, and polyvinyl pyrrolidone)syrup, sodium alginate, and polyvinyl pyrrolidone)
Lubricants (to pass through the gastrointestinal tract without sticking;
lubricants include magnesium stearate, stearic acid, talc,
colloidal silica, and polyethylene glycol)
Disintegrants (to be absorbed in the small intestine; disintegrants
include starch, alginic acid, and sodium lauryl sulphate )
Colouring agents
Flavoring agents
Drug Names
Drugs have three or more names including a:
chemical name (according to rules of nomenclature),
brand or trade name (always capitalized and selected by the
manufacturer)
generic or common name (refers to a common established
name irrespective of its manufacturer).
In most cases, a drug bearing a generic name is equivalent to the
same drug with a brand name. However, this equivalency is not
always true. Although drugs are chemically equivalent, different
manufacturing processes may cause differences in pharmacological
action. Several differences may be crystal size or form, isomers,
crystal hydration, purity-(type and number of impurities), vehicles,
binders, coatings, dissolution rate, and storage stability.
Drugs design (for connecting diseases to molecules) may be
elaborated according to several approaches:
THE PHYSIOLOGICAL SYSTEMS APPROACH
(the same organizational lines as conventional medicine)
Focused on the ten fundamental physiological systems of the human body and the
particular diseases associated with these systems:
1. Cardiovascular system
2. Dermatological system
3. Endocrine system Disease
3. Endocrine system
4. Gastrointestinal system
5. Genitourinary system
6. Hematological system
7. Immune system
8. Musculoskeletal system
9. Nervous system
10. Respiratory system
It is not ideal in connecting “disease to molecule.” For example, when designing
drugs for the cardiovascular system, many different receptors (adrenergic,
cholinergic) and many different pathological processes (atherosclerosis,
inflammation) are involved.
biochemical and
molecular processes
involved in disease
THE PATHOLOGICAL PROCESS APPROACH
This classification system is based on a traditional pathology approach to
disease with emphasis on etiology (causative factors) and pathogenesis
(mechanism of disease, particularly at a cellular level). This approach focuses
on ten fundamental pathological processes:
1. Traumatic (pathology from injury)
2. Toxic (pathology from poisons)
3. Hemodynamic/vascular (pathology from disorders of blood vessels)
4. Hypoxic (pathology from inadequate supply or excessive demand for oxygen by
a tissue)a tissue)
5. Inflammatory (pathology from abnormal inflammatory response in the body)
6. Infectious (pathology from microbes or infectious agents)
7. Neoplastic (pathology from tumors, cancer)
8. Nutritional (pathology from too much/too little food intake)
9. Developmental (pathology in the chemistry of heredity)
10. Degenerative (pathology from age-related tissue breakdown)
+: drug design that targets a pathology (e.g. neoplasia) may lead to drugs with
many applications, (e.g. lung cancer, bowel cancer, or brain cancer).
- this approach focuses more on cellular targets than on molecular targets.
THE MOLECULAR MESSENGER AND NONMESSENGER TARGET SYSTEM
A third conceptual approach, is to focus on the biochemical and molecular
processes of human disease. It may be classified as follows:
1. Messenger targets I—Neurotransmitters (fast messengers),
2. Messenger targets II—Hormones (intermediate messengers), such as the
Steroid hormones and their receptors and the Peptide hormones and
their receptors
3. Messenger targets III—Immunomodulators (slow messengers), such as the 3. Messenger targets III—Immunomodulators (slow messengers), such as the
Immunosuppressants and their receptors and the
Immunomodulators/immunostimulants and their receptors
4. Non-messenger targets I—Endogenous cellular structures, such as Membrane
targets , Nuclear targets, etc.
5. Non-messenger targets II—Endogenous macromolecules, such as Proteins ,
Nucleic acids, Lipids, Carbohydrates, etc
6. Non-messenger targets III—Exogenous pathogens, such as Microbes ,
Environmental toxins , etc