e-content of Biological drug targets for M.pharm students

1. BIOLOGICAL DRUG TARGETS
Presenting by:
Mr. Purushotham K N
Asst. Professor
Department of Pharmaceutical
Chemistry
SACCP,B.G.Nagara
2021-2022
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2. CONTENTS
1. Introduction to Biological drug targets
2. Receptors
3. Types of the receptors
4. Drug-Receptor Interactions
5. Theories of drug receptor Interaction
6. Artificial Enzymes
7. Agonist V/S Antagonist
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3. INTRODUCTION
• Drugs produce their therapeutic effects by producing biochemical or physical
changes in the targeted tissues of the host.
• To get the desired pharmacological action, it is essential that:-
 Sufficient concentration of drug reaches the site of action and remains their
for a sufficient duration and the tissue is susceptible for drug action.
• The magnitude of drug action is proportional to the concentration of drug at the
site of action.
• Receptor mechanism is very important to understand the action and effect of a
drug 3

4. BIOLOGICAL DRUG TARGETS
• The term “biological target” is frequently used in pharmaceutical research to
describe the natural protein in the body whose activity can be modified by a
drug that results in a specific effect, which may be a desirable therapeutic
effect or an unwanted adverse effect.
• Within a living organism, a drug or an endogenous ligand is directed and/or
binds, resulting in a change in its behavior or function.
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5. Mechanism
• The external stimulus physically binds to the biological targets.
• The interaction between the substances and the target may be;
Reversible covalent- A chemical reaction occurs between the stimulus and target in
which the stimulus becomes chemically bonded to the target, but the reverse
reaction also readily occurs in which the bond can be broken.
Irreversible covalent- The stimulus is permanently bound to the target through
irreversible chemical bond formation.
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6. • Omeprazole is a selective irreversible proton pump inhibitor. It
suppresses stomach acid secretion by specific inhibition of H+ /
K+ ATPase found on the secretary surface of gastric parietal
cells.
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7. RECEPTORS
• When the drug is taken, it travels through the body to a target site and elicits a
pharmacological effect. The site of drug action, which is ultimately responsible for
the pharmaceutical effect, is a receptor. The binding of drug to a receptor
constitutes pharmacodynamics.
• The term “receptor” was first introduced in 1907 by Paul Ehrlich who said
compounds do not act unless bound.
• Receptors are mostly membrane bound proteins that selectively bind small
molecules, referred to as ligands, that elicit some physiological response.
Receptors are generally integral proteins that are embedded in the phospholipid
bi-layer of cell membranes.
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8. • Lipoproteins- these are often embedded
in the plasma membrane or cell organelle
membrane as intrinsic proteins.
• The binding of the chemical messenger
causes the receptor to change shape,
initiating a process that result in a message
being received by the cell.
•Occupation of a receptor by a drug
molecule may or may not result in the
activation of the receptor departs
unchanged, allowing the receptor to reform
its original shape.
Polar end
groups
Hydrocarbon
chains of the
lipids

9. TYPES OF RECEPTOR
• Type 1: Ligand-gated ion channels
• Type 2: G-protein-coupled receptors
• Type 3: Kinase-linked receptors
• Type 4: Nuclear receptors
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10. Ligand-gated ion channels:
• The ligand-gated ion channels are also known as ionotropic receptors.
• Ion channels are protein complexes present transversely on the cell membrane and form a tunnel
like structure.
• The function of an ion channel is to allow the flow of ions across the cell membrane and there are
specific ion channels for Na, K, Ca and chloride ions.
• Without these ion channels, ions could not cross the fatty cell membranes and the ion channels
cannot be permanently open, uncontrolled flow ions across the membrane would be devastating.
• The receptor controls the ion channel opening and closing.
• In the resting state, ion channel is closed and receptor binding site is unoccupied and when the
chemical messenger binds to the receptor , proteins on the cell membrane alters their position
results in opening up of ion channel and ions flow through the channel.
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11. • Once the chemical messenger leaves the receptor, the receptor and ion
channel reform their original shapes and block off the flow of ions. Such
receptors are called ligand-gated ion channel receptors because the
trigger for the process is a chemical messenger (drug), and the effect is to
open up the ‘gate’ sealing the ion channel.
• Examples: Nicotinic acetylcholine receptor, GABA -a RECEPTORS
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12. • Nicotinic acetylcholine receptor mediates transduction of chemo-
electric signals throughout the nervous system by opening an
intrinsic ion channel.
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13. G-protein-coupled receptors:
• These receptors so named because the receptor conveys a signal to the cell via
a signalling protein called a G-Protein.
• The G-protein coupled receptor contain binding site for the ligand present
extracellularly. However, there is a second binding site on the intracellular
region of the receptor which is specific for the G-protein.
• The G-protein is made up of 3 subunits α, β, γ and is free to move through the
cell membrane.
• Examples: Muscarinic receptors (feedback regulation of Ach release), beta
adrenergic receptors
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14. G-protein coupled receptors, this consists of 5 main steps.
1) Ligand bind to the extracellular portion of the G-protein coupled receptor, binding
either at the N-terminus or a binding site within the transmembrane region.
2) Binding at the extracellular ligand binding site causes a conformational change in
the GPCR, resulting in release of GDP from the α-subunit of the G-protein.
3) Released GDP is then replaced with a GTP
4) This activates the G-protein, causing the α-subunit and bound GTP
to dissociate from the transmembrane portion of the GPCR and βγ-subunit.
5) These α-subunit interacts with its relevant effectors and cause downstream
effects, e.g. ion channel opening or enzyme activity regulation.
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15. • To prevent excess signaling, GPCR activity can be switched
off. GTPase catalyses the breakdown of GTP on the α-subunit into GDP + Pi.
GDP increases the α-subunit’s affinity for the β γ-subunit, allowing
reformation of the heterotrimeric complex of the G-protein. The G-protein
then re-associates with the transmembrane receptor, reforming the GPCR
for the next ligand binding.
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17. Kinase-linked or enzyme-linked receptors:
• These receptors are similar to that of G-
protein coupled receptor and it has an
extracellular region and an intracellular
region.
• The extracellular region acts as the receptor
and has a binding site for chemical
messenger.
• The intracellular region acts as a tyrosine
kinase enzyme and has an active site.
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20. Nuclear receptors:
• Nuclear receptors are activated by lipid soluble signals.
• Unlike most intercellular messengers, the ligand can cross the plasma
membrane and directly interact with nuclear receptors inside the cell
• The nuclear receptors regulate the gene transcriptions once they activated that
controls a wide variety of biological processes, including cell proliferation,
development, metabolism and reproduction.
• The receptor protein is inherently capable of binding to specific genes. These
include the receptors of glucocorticoids and thyroid hormone.
• Example: Steroids (estrogen and progesterone) and thyroid hormones
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21. THEORIES OF DRUG
RECEPTOR INTERACTIONS
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22. CLASSIFICATION OF LIGANDS
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LIGAND

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• Where, kon is the rate constant for formation of the
drug-receptor complex, which depends on the
concentration of the drug and the receptor.
• Koff is the rate constant for break down of the
complex, which depends on the concentration of the
drug-receptor complex as well as other forces.
• The biological activity of the drug is related to its
affinity for the receptor, i.e., the stability of the drug-
receptor complex.
• This stability is commonly measured by how
difficult is for the complex to dissociate, which is
measured by its kd , the dissociation constant for the
drug-receptor complex at equilibrium.

25. Occupation Theory
Proposed by Gaddum and Clark, the theory states that the intensity of
pharmacological effect is directly proportional to the number of
receptors occupied by the drug. The response ceases when the drug-
receptor complex dissociates.
• The pharmacological response of a drug molecule depends on the
amount of dose, the total number of receptors available, and its intrinsic
activity or efficacy.
• Not all agonist produce a maximal response. Therefore, this theory does
not rationalize partial agonists and it does not explain inverse agonist.
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26. • Ariens and stephenson modified the occupancy theory to account for partial
agonists.
• The drug-receptor interactions involve 2 stages: First, there is a complexation
of the drug with the receptor, which they termed as affinity; second, there is an
initiation of biological effect termed as intrinsic activity or efficacy. The
original theory consider these properties as constant.
• Affinity is a measure of the capacity of a drug to bind to the receptor, and is
dependent on the molecular complementarity of the drug and the receptor.
• Intrinsic activity refers to the maximum response induced by a compound.
•A compound that is an agonist for one receptor may be an antagonist or
inverse agonist for another receptor.
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27. • A compound that elicits the maximum response is a full agonist; a particular
compound may be capable of exceeding the maximum response of a tissue, but the
observed response can only be the maximum response of that particular tissue.
• A drug that is not capable of eliciting the maximum response of the tissue is a
partial agonist and full and partial agonist show positive efficacy.
• Antagonist displays zero efficacy, and a full or partial inverse agonist displays
negative efficacy (below basal tissue response).
LIMITATION: This modified occupancy theory applicable for the existence of partial
agonists and antagonists, but it does not explain why two drugs that can occupy the
same receptor can act differently, i.e., one as an agonist, the other as an
antagonist.
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28. The Rate Theory
• As an alternative to the occupancy theory, Paton proposed that the activation
of receptors is proportional to the total number of encounters of the drug
with its receptor per unit time. i.e., the response is proportional to the
rate of drug-receptor complex formation.
• Response depends on the rate of association and dissociation of the
drug with the receptor, and not the number of occupied receptors that
determines whether the molecule is a agonist or partial agonist.
• Similar to occupancy theory, it also does not give any information regarding
the different types of compounds exhibit the characteristics that they do.
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29. Induced Fit Theory
• It is proposed by Koshland to give explanation for the action of enzymes and
substrates. It explains that the receptor (enzyme) need not necessarily exist
in the same conformation that is required to bind the drug (substrate).
• As the drug approaches the receptor, a conformational change is induced for
binding, which is responsible for the pharmacological activity.
• The conformational change need not to be occur only in receptor; the drug also
could undergo deformation.
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30. • For example, Ach interacts with the receptor protein produces temporary
rearrangement in membrane structure and a consequent change in its ion
regulating property. Since these receptors are elastic and return to the
original conformation after the drug releases.
• According to this theory, an agonist will bind by conformational change with
intrinsic activity and elicit a response, but an antagonist will bind by
conformational change without efficacy.
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31. Macromolecular Perturbation Theory
• According to this theory, the drug interaction with a receptor leads either to
specific conformational perturbations (SCPs) or to nonspecific
conformational perturbations (NSCPs).
• An SCP will produce a specific response from an agonist in which the drug
possesses intrinsic activity(an agonist). In NSCP, no stimulant action, but may be
antagonistic or blocking action will be produced.
• If a drug possesses SCP and NSCP features, an equilibrium mixture of two
complexes may result and leads to partial agonistic action.
• This theory does not address the concept of inverse agonism.
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32. Activation–Aggregation Theory
• According to this theory, even in the absence of drugs, a receptor is in a state
of dynamic equilibrium between an activated form (Ro) and an inactive form
(To), which is responsible for biological responses.
• Agonists shift the equilibrium to activated form and antagonists shift the equilibrium
to inactivated form.
• Partial agonists bind to both conformations during partial antagonistic action. The
agonist-binding site and antagonist-binding site conformation may be different.
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33. Artificial Enzyme
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• An artificial enzyme is a synthetic, organic molecule or ion that recreate some
function of an enzyme (enzyme mimics).
• Protein engineering technologies has developed to design and synthesize molecules
with the activities of enzyme for non-natural reactions.
• They could even be used as replacements for certain natural enzymes that are more
complex and difficult to produce on a large scale.
• A number of possibilities now exist for the construction of artificial enzymes. These
are generally synthetic polymers with enzyme –like activities, often called
SYNZYMES.

34. • Advances in the fields of molecular biology, biochemistry and
more recently combinatorial & polymer chemistry provide co-
operative solutions to the synthesis of artificial enzymes.
• Cyclodextrins, Crown ethers and calixarene are some of the
examples for the artificial enzyme technique.
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35. REFERENCES
1. Textbook of Organic Chemistry of Drug Design and Drug Action
by RICHARD B. SILVERMAN. (123-140)
2. Textbook of Medicinal Chemistry Vol-1 by ILANGO
VALENTINA. (8-21)
3. Textbook of Medicinal Chemistry Vol-1 by S. Pandeya. (16-27)
4. Textbook of Medical Pharmacology by K. D. Tripathi.
5. Textbook of Biochemistry by U. Satyanarayana
6. https://en.m.wikipedia.org>wiki>artificialenzyme
7. Sutanto F, Konstantinidou M, Dömling A. Covalent inhibitors: a
rational approach to drug discovery. RSC Med Chem. 2020 Jul
2;11(8):876-884. doi: 10.1039/d0md00154f. PMID: 33479682;
PMCID: PMC7557570.
8. Motherwell, W. B., M. J. Bingham, and Y. Six. "Recent progress in
the design and synthesis of artificial enzymes." Tetrahedron 57.22
(2001): 4663-4686.

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