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