DRUG DISCOVERY
Drug Discovery without a lead
LEAD DISCOVERY/IDENTIFICATION
LEAD MODIFICATION
CONCEPT OF PRODRUGS AND SOFT DRUGS
DRUG RECEPTOR INTERACTIONS
1. Dr. BASAVARAJAIAH S. M.
Assistant Professor and Coordinator
P.G. Department of Chemistry
Vijaya College
Bangalore-560 004
BASICS CONCEPTS OF MEDICINAL
CHEMISTRY
2. Contents
DRUG DISCOVERY
Drug Discovery without a lead
LEAD DISCOVERY/IDENTIFICATION
LEAD MODIFICATION
CONCEPT OF PRODRUGS AND SOFT DRUGS
DRUG RECEPTOR INTERACTIONS
7. DRUG DISCOVERY
Drug discovery is a very time-consuming and expensive
process.
Estimates of the average time required to bring a drug to the
market range from 10-12 years and at an average cost of $600-
800 million.
For approximately every 10, 000 compounds that are evaluated
in animal studies, 10 will make it to human clinical trials in order to
get 1 compound on the market.
In general, drugs are not discovered. What is more likely
discovered is known as a lead compound.
8. The lead is a prototype compound that has a number of
attractive characteristics, such as the desired biological or
pharmacological activity, but may have other undesirable
characteristics, for example, high toxicity, other biological
activities, insolubility, or metabolism problems.
The structure of the lead compound is modified by synthesis
to amplify the desired activity and to minimize or eliminate the
unwanted properties to a point where a drug candidate.
Prior to lead discovery and lead modification, two common
drugs discovered without a lead are discussed.
13. LEAD DISCOVERY/IDENTIFICATION
Generally following steps are involved in lead discovery
1. Random screening
2. Non-random/Targeted/Focus screening
3. Drug metabolism studies
4. Clinical observations
5. Rational approaches
14. 1.RANDOM SCREENING
In the approach of known drugs and other compounds with
desired activity, a random screen is a valuable approach.
Random screening involves n intellectualization; all compounds
are tested in the bioassay without regard to their structures.
This is the lead discovery method of choice when nothing is
known about the receptor target.
Streptomycin Tetracycline
15. 2. NON-RANDOM/TARGETED/FOCUS SCREENING
Non-random screening is a more narrow approach than is
random screening.
In this case, compounds having a vague resemblance to weakly
active compounds uncovered in a random screen.
Random screen was modified to a nonrandom screen because
of budgetary and manpower restrictions.
16. 3. DRUG METABOLISM STUDIES
During drug metabolism studies, metabolites that are isolated are
screened to determine if the activity observed is derived from the
drug candidate or from a metabolite.
Sulindac Reduced form
(Antinflammatory agent)
17. 4. CLINICAL OBSERVATIONS
Sometimes a drug candidate during clinical trials will exhibit
more than one pharmacological activity; it may produce side
effect.
This compound, then, can be used as a lead for the secondary
activity.
Dimenhydrinate (Antihistamine) after clinical observations
showing that treatment for motion sickness.
Bupropion is a antidepressant drug, Clinical
studies showed that smoking Cessation aid.
18. 5. RATIONAL APPROACHES
Rational approaches to drug design now have become the
major routes to lead discovery.
The knowledge about the receptors and their mode of
interaction with drug molecules plays am important role in drug
design.
This idea maybe used to develop confirmationally bioactive
skeletons having exact three dimensional complementarity to a
receptor.
Greater potency, higher selectivity and less adverse effects are
expected by reducing the flexibility of the drug structure.
19. Serotonin Indomethacin
Ex.1: Serotonin was used as lead for anti-inflammatory agents,
and from this drug Indomethacin was developed.
Progesterone
17- Ethinyl estradiol
Norgestrel
Contraceptive drug
Ex.2:
20.
21. Any drug molecule consists of both, essential and non-essential
parts.
Essential part governing the pharmacodynamics property (D-R
interactions).
Non-essential part governing the pharmacokinetics property
(ADME).
The schematic representation of nature of such bioactive
functional groups along with their inter-atomic distance is known
as pharmacophore.
1. IDENTIFICATION OF ACTIVE PART (PHARMACOPHORE)
22. Auxophore: Other atoms in the lead molecule, may be
extraneous which may be interfering with the binding of
pharmacophore.
Structural modification can be done to improve pharmacokinetic
properties of the drugs.
For example: The presence of a phenyl ring, asymmetric
carbon, ethylene bridge, and tertiary nitrogen are found to be
minimum structural requirements for a narcotic analgesic to
become active.
24. 2. FUNCTIONAL GROUP OPTIMIZATION
The activity of a drug can be correlated to its structure in terms
of the contribution of its functional groups to liphophilicity,
electronic and steric factors.
Hence, by selecting proper functional groups, one can govern
the drug distribution pattern and can avoid the occurrence of side
effects.
Chlorothiazide
Dazoxide
Only Antihypertensive activity Antihypertensive activity
Diuretic activity
25.
26. 3. Structure-Activity Relationship (SAR)
Structure-Activity Relationship (SAR) studies usually
involves the interpretation of activity in terms of the
structural features of a drug molecules.
27. Ex: SAR studies of Sulfonamides drugs
The following conclusions are made;
45. 2. Effect of ionization:
Electronic effects:- The Hammett equations
46.
47.
48.
49.
50.
51.
52. CONCEPT OF PRODRUGS AND SOFT DRUGS
PRODRUGS
A prodrug is a inactive compound that is converted into an
active drug by a metabolic biotransformation (Usually hydrolysis).
Instead of administering a drug directly, a corresponding
prodrug can be used to improve how the drug is absorbed,
distributed, metabolized, and excreted (ADME).
Prodrugs are often designed to improve bioavailability when a
drug itself is poorly absorbed from the gastrointestinal tract.
PRODRUG DRUG
Invivo
53. Ex:
Aspirin Methyl salicylate Phenyl salicylate
All the above 3 compounds (prodrugs) on hydrolysis give
salicylic acid (Active drug).
In order to state that prodrug formation has occurred, evidence
must be provided that original drug has been liberated in vivo.
The prodrug is not responsible for the activity and should be
benefit of biological activity.
54. PRODRUG DESIGN or DRUG LATENTIATION
There are 3 main phases of drug action, namely,
The pharmaceutical (Formulation).
The Pharmacodynamic (Drug-Receptor Interactions).
Pharmacokinetics (ADME)
Problems exist in all three phases.
Prodrug formation seeks to address the problem in the
pharmaceutical and pharmacokinetic phases.
It does not address the Pharmacodynamic phase problems.
Drug latentiation is the chemical modification of a biologically
active compound to form a new compound, which in vivo will
liberate the parent compound.
55. These drawbacks includes;
Unpleasant taste and odor
High acidity
Poor hydrophilic
Instability
Shorter duration of action
Site non-specificity
Poor absorption-distribution
Less attractive color
Prodrug designing is required to overcome these problems.
62. 1. Non-intentional prodrug:
Sometimes, after administration of the drug the metabolic
studies indicate the prodrug nature of drug.
It becomes accidentally evident that the activity of a drug is
because of its metabolite and not because of the parent drug.
Sulindac (Prodrug) Reduced form (Drug)
(Antinflammatory agent)
73. SOFT DRUGS
Soft drugs (antedrugs) are biologically active drugs designed to
have a predictable and controlled metabolism.
Soft drugs are metabolism to nontoxic and inactive products
after they have achieved their desired pharmacological effect.
Ex: Drugs acting on specific areas in the eye, brain and testes
etc.
74. ADVANTAGES OF SOFT DRUGS
Elimination of toxic metabolites, thereby increasing the
therapeutic index of the drug.
Avoidance of pharmacologically active metabolites that can lead
to long term effects.
Elimination of drug interactions resulting from metabolite
inhibition of enzymes.
Simplification of pharmacokinetic problems cause by multiple
active species.
75. PROPERTIES OF SOFT DRUGS
It has close structural similarity to the lead.
It is a metabolically sensitive moiety built into the lead structure.
The sensitive part does not affect the overall physiochemical or
steric properties of the lead compound.
Soft drug metabolism rate can be predictable and controllable.
Metabolic products of soft drugs are nontoxic and have no
other biological activities.
Soft drug metabolic products does not give to highly reactive
intermediates.
76.
77. HARD DRUGS
Hard drugs are nonmetabolizable compounds, characterized
either by high lipid solubility.
They are poor substrates for the metabolizing enzymes.
They bind strongly to receptor site and do not easily excreted
out of the system.
When they excrete, they destroy the receptor sites.
Continous usage of hard drugs leads to addiction.
Heroin Nimesulide
78. ANALOGS
Analog design is usually defined as the modification of a drug
molecule or of any bioactive compound in order to prepare a new
molecule showing chemical and biological similarity with the
original model compound.
Analogs are primarily prepared synthetically to increase the
potency of the original drug or resistance of the parental drug.
Pencillin G
Amipicillin Amoxyllin
94. OCCUPANCY THEORY
Proposed by Gaddum and Clark.
The intensity of the pharmacological effect is directly
proportional to the number of receptors occupied by the drug.
The pharmacological response of a drug molecule is a function
of dose, number of receptor available and its intrinsic activity.
The rate of combination of drug and receptor can therefore be
expressed as; K1 [R] [A]
Where K1 = Association constant R= Concentration of
unoccupied receptor, A= Concentration of drug.
95. Similarly, K2 [RA]
Where K2 = Dissociation constant RA= Concentration of
occupied receptor, A= Concentration of drug.
At equilibrium,
K1 [R] [A]= K2 [RA]
If [R] + [RA] = r (Concentration of receptor) &
K2/K1=KA (Eq. constant)
When RA=r ie all the receptors are occupied and the response is
thus proportional to its intrinsic activity (Xn or ).
96. Drawbacks:
This theory does not account for partial agonist and antagonist.
Ariens and Stephenson modified the occupancy theory to
account for partial agonist.
They coined the terms affinity and efficacy/intrinsic activity.
It does not account for why two drugs that can occupy the same
receptor can act differently i.e. one as an agonist, the other as an
antagonist.
97. RATE THEORY
Paton and Rang proposed the rate theory.
They proposed that the activation of receptors is proportional to
the total number of encounters of the drug with its receptor per
unit time.
Therefore, the rate theory suggests that the pharmacological
activity is a function of the rate of association and dissociation of
the drug with the receptor, and not the number of occupied
receptors.
Each association would produced a quantum of stimulus.
In the case of agonists, the rate of association is slow and
dissociation rate would be fast.
98. In the case of antagonist, the rate of association is fast and
dissociation rate would be slow.
At equilibrium, the occupancy and rate theory mathematically
equivalent.
As in the case of the occupancy theory, the rate theory does not
rationalize why the different types of compounds exhibit the
characteristics that they do.
99. INDUCED FIT THEORY
The induced fir theory of Koshland was originally proposed for
the action of substrates and enzymes, but it could apply to drug-
receptor interaction as well.
According to this theory the receptor need not necessarily exist
in the appropriate conformation required to bind the drug.
As the drug approaches the receptor, a conformational change
is induced that orients the essential binding sites.
The conformational change in the receptor could be responsible
for the initiation of the biological response.
The receptor was suggested to be elastic, and it could return to
its original conformation after the drug was release.
100. The conformational change need not occur only in the receptor;
the drug also could undergo deformation.
According to this theory, an agonist would induce a
conformational change and elicit a response.
An antagonist would bind without a conformational change.
A partial agonist would cause a partial conformational change.
101. MACROMOLECULAR PERTURBATION THEORY
Belleau suggested that in the interaction of a drug with a
receptor two general types of macromolecular perturbations could
result;
Specific perturbations –Biological response (Agonist).
Non-specific perturbations –No biological response (Antagonist).
This theory offers a physicochemical basis for the rationalization
of molecular phenomena that involve receptors.
This theory does not address the concept of inverse agonism.
