Lecture 22
Medicinal Chemistry 1
Lana Hammad
 Models of drug-receptor interactions (Drug-Receptor interaction theories):
1) Occupancy theory : the ability of a drug to occupy a receptor to cause an effect
(Affinity & intrinsic effect)
- it doesn’t explain the inverse agonist activity, nor does it explain the antagonist activity
properly 2) Rate theory : it is a modification of the occupancy theory , so instead of the number
of receptors associated with a drug molecule, we look at the rate of association and
dissociation of the drug to the receptor.
 Agonist : Rate of association = Rate of dissociation (both are fast)
 Antagonist : rate of association > rate of dissociation (it associates with the receptor at
a high rate, but takes longer time to dissociate )
-The higher the rate of dissociation the greater response we get , so when we lower the
rate of dissociation, we get lower response (antagonism)- (here response means the
normal activity not response to the drug action)
3) Induced- fit theory :
Here we consider conformational changes of the receptor ,
 Agonist  causes conformational changes
 Antagonist  doesn’t cause conformational changes
-we cannot explain the inverse agonist activity in this theory –
4) Macromolecular Perturbation theory :
There’s a specific conformation for an agonist , and all other non-specific conformations are
for antagonist s.
(more than one conformation, and only one is active, the rest are all inactive)
5) Activation aggregation theory :
Active form has a Specific conformation (specific for agonists) , and the inactive
form also has another specific conformation(specific for antagonists)
-this theory didn’t explain the inverse agonist activity-
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Lecture 22
Medicinal Chemistry 1
Lana Hammad
6) Two state (multistate) model:
Active state and resting state (like muscle drugs, it can be an agonist for contraction
or it can block a certain receptor by keeping it at the resting state)
-there is a multistate model (two active conformations and one inactive for an example)## we don’t have a universal model that explains all drug activities, each model explains a
certain aspect of drug activity ##
## the importance of these theories is to differentiate between agonist and antagonist
activity, since they both bind to similar binding pockets , but each one gives a different
activity ##
 Quantification of drug-receptor activity:
(we mentioned earlier that the problem with receptors in drug discovery is that we
can’t isolate them, because we can’t test the membrane potential if we separate the
protein from the cell, since its function won’t be measurable, and because they cant be
isolated we don’t have a clear idea of their structure therefore the function isn’t clearly
known)
 Law of mass action : chemical equilibrium
--- two direction equilibrium constants:
Koff
Drug
+
Receptor
Complex
Kon
 K on : is the constant when the drug is bound to the receptor,
K off: is the constant when the drug is dissociated from the receptor.
we can estimate the rate of association = [receptor]*[ligand]*Kon
* the higher the value of Kon the higher the rate of association
we can also estimate the rate of dissociation = [ligand-receptor complex]*Koff
* the higher the value of Koff the higher the rate of dissociation
at equilibrium , the equilibrium constant will be
 Kd= [ligand] *[receptor]/[complex]
Kd is the concentration of ligands that associates with half of the receptors at
equilibrium
the lower the value of Kd the higher the rate of association (higher conc. Of complex +
higher affinity )
unit of Kd = concentration unit
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Lecture 22
Medicinal Chemistry 1
Lana Hammad
Kd has a different unit and meaning than Kon and Koff , Kd is an equilibrium
constant, while Kon and Koff are association and dissociation constants
respectively.
# the more complicated a system is, the more complicated these equations would be #

Types of drug targets:
30000 genes, 1\3 of these targets(10000) are “drugable” which means they have a site
for drug interaction . Only 500 out of 10000 targets are used as drug targets, so we
have a gap between the number of diseases that we can treat and the number of genes
involved in diseases
Research should be done in order to understand the function of targets that we still
don’t use as drug targets
- G-protein coupled receptors :
-membrane embedded ,, most of the effective drugs work on these receptors
(drugs involved in cardio diseases, cancer, asthma, gastrointestinal and CNS
diseases work on these receptors)
-200 out of 1000 of these receptors are of known function, the rest are “orphan”
targets
orphan GPCR  of unknown origin and function (biological function \drugability)
# biological activity is complicated because several second messengers and
reactions take place#
-using this property, drugs are designed as agonists, inverse agonists, and
antagonists according to which second messenger they activate
 beta receptors, adrenergic, hypertension drugs, asthma drugs  used as
antagonists
 drugs that work on opiates for pain relief (opiate-like molecules),beta receptors
 used as agonists
# the problem with GPCR’s is “tachyphylaxis” which is is a medical term describing an
acute (sudden) decrease in the response to a drug after its administration
# drugs that treat depression or work on serotonin usually interact indirectly with GPCR’s
# natural ligands that bind to these receptors can be very diverse: small organic molecules,
peptides, amines, lipids, phospholipids, purines,amino acids, nucleotides.
the development of drugs that we bind to these receptors is complicated
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Lecture 22
Medicinal Chemistry 1
Lana Hammad
for an example:
peptides: GLP (glucagon like peptide):
Exenatide is a glucagon-like peptide-1 agonist (GLP-1 agonist) medication, belonging to
the group of incretinmimetics, approved for the treatment of diabetes mellitus type 2, it is
found found in the saliva of a certain snake, It displays biological properties similar to
human glucagon-like peptide-1 (GLP-1), a regulator of glucose metabolism
and insulin secretion.(induce hypoglycemia)
Exenatide is a 39-amino-acid peptide, an insulin secretagogue, while GLP is a 37-amino-
acid peptide
*Q: is the fact that GPCR’s work on several systems and parts of the body a positive or a
negative thing?
it is an advantage for the body because it builds one type of receptor to achieve many
functions, and with limited facilities we have less chance of error. As for those who
create drugs, it makes it a harder job to get a specific drug with fewer side effects
structural features:
Structurally, GPCRs are characterized by an extracellular N-terminus, and an intracellular Cterminus
N-terminus: NH2
C-terminus : COOH
possess seven membrane-spanning domains or transmembrane helices connected to
extracellular and intracellular loops
## amino acids are connected by peptide bonds (amide NH2-COOH)
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Lecture 22
Medicinal Chemistry 1
Lana Hammad
-the interaction of second messenger usually occurs around the C-termini and the
ligand interacts with the receptor at the area between the N-termini and the
extracellular loops
we can classify them to different classes depending on their structure:
(usually the N-terminus makes the difference)
Class A: (Rhodopsin-like)  the N-terminus is short (extracellular)m they can interact with
several small ligands, such as peptides , glycoprotein and proteins
-rhodopsin , beta adrenergic receptors  they know their structure, and the scientists who
discovered their structure won a Nobel prize
Class B: (Secretin receptor family)  the N-terminus is longer (extracellular domain)
mostly hormones, GLP , glucagon , calcitonin , those hormones have hormonal activity and they
control the development of the body and regulation of metabolism.
(example: GLP not only affects glucose level, it also affects lipid levels in the body, and can
reduce the appetite  it is a collaboration between several actions)
## Note: many companies make drugs based on their knowledge of the structure of the
extracellular domain ##
Class C: (Metabotropic glutamate/pheromone)  more disulphate bond
mainly in the CNS, for glutamate and gamma receptors.
usually small ligands bind to receptors of this class (gamma, magnesium, pheromones, taste
molecules)



-
Ion channels :
works through changes in membrane potential,
(transduction of muscle contraction, secretion of hormones, neural signals, and most
biological processes are affected by membrane potential)
we can classify them to two types:
* voltage gated:
interaction involves small ions transfer
they are membrane proteins that are hard to study,
most of them are sodium-ion channels, or calcium-ion channels, or potassium-ion
channels
their structure is very complex
they are important in cardiovascular treatments
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Lecture 22
Medicinal Chemistry 1
Lana Hammad
* ligand gated :
serotonin, glutamate, gaba, cholinergic
found in neurons, muscles, ganglia, lymphocytes, ceratinocytes, pancreatic cells, etc.
structure is simpler than voltage gated.
-
Enzymes:
such as reductases-oxydases \ proteases \phosphodiesterases(like diabetes
drugs)\kinases(cancer drugs inhibit these)
the C-terminus is the part with catalytic activity, and the N-terminus has the regulatory
activity
their structure is easier to study
* Phosphodiesterases: (esterase)
-they cleave the phosphate bond
-very important in the activation of second messenger and work on cyclic AMP &
cyclic GMP ,
(by inhibiting the second messenger we inhibit the activity of GPCR indirectly)
their inhibition has several applications ; diabetes , auto immune diseases, obesity.
*Kinases: (phosphorylation of protein molecules)
-very important in cancer therapy, because their inhibition affects cell growth and
biological processes (New anticancer drugs: Imatinib, Ibrutinib)
-there is a large number of kinases, and we still don’t know the biological activity of
many of them,
-there are different classes of kinases, such as serine/threonine kinase , & tyrosine
kinases
-they work on inflammatory reactions, immune reactions, affect metabolism
-used for diabetes & obesity: tyrosine phosphatase, and phosphatase
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Lecture 22
-
Medicinal Chemistry 1
Lana Hammad
Nuclear hormone receptors:
a lot of drugs work on these receptors, especially in the case of hormone deficiency
(agonist is used) or when there is hormone over-secretion (antagonist is used)
sometimes if cancer is related to a hormone, these receptors are targeted :
* estrogen-related cancer  block estrogen secretion
drugs that interact with these receptors usually affect development, physiological &
metabolic processes (thyroid , vitamin-D , steroids , estrogen, tamoxifen )
there are different classes of hormonal receptors :
class 1: steroidal hormones
class 2: thyroid hormone
class 3: orphan receptors
Q: how do we know that this class is related to hormone receptors if they are orphan?
from the sequence of amino acids (certain segments that relate them to each other)
“We all fight battles that no one
knows except Allah.
Just remember, He knows all and
He can help with all.”
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