Download Drug Targets

‫محمد نورالدين محمود‬
‫كيمياء دوائية (‪)1‬‬
Drug targets
• Drug targets are usually functional macromolecules
(mainly proteins but can be others like DNA, etc.) involved
in specific biological action.
• Drug targets can be referred as receptors (Targets=Receptors).
• The interaction of drug molecule with those targets will
produce biological response.
• Drugs usually disturb the normal function of the targets
 biological effect.
• For a drug to selectively disturb the function of a
particular target, it should bind selectively to the target.
Nothing is better than mimicking the specific substrate of
that target.
• The substrate and the drug bind to specific site on the
macromolecule known as the ‘binding site’.
• Most drugs disturb the normal biochemical reactions.
‫معظم االدوية هي عبارة عن مواد معطلة للتفاعالت العادية داخل الجسم‬
Specific receptors
• Drug targets are macromolecules of various structures, functions and intracellular locations.
• The drug targets can be classified mainly into:
1.
Enzymes
e.g. angiotensinogen
converting enzyme
2.
G-protein coupled receptors
e.g. β-adrenergic receptors
3.
Ion channels
e.g. calcium channels
4.
Nuclear receptors
e.g. insulin receptor
Hopkins, A.L. and Groom, C.R., 2002. The druggable genome. Nature reviews Drug discovery, 1(9), pp.727-730.
Intermolecular interaction between drug and target
• The strength of drug-target interaction is measured as energy (Kcal/Mol). Which means the
amount of energy required to separate them away from each other.
• Some drug-target interactions are so strong, and are due to the formation of covalent bond (200-400
Kj/Mol). Such drugs are long acting drugs
• Some drug-target interactions are weak, and are due to non-covalent bonds (H-bonds, electrostatic,
ionic, van der Waals, dipole-dipole and hydrophobic interactions). Such drugs are short acting drugs.
• The energy of drug-target interaction determines
the time period the drug occupies target binding
site (which can be measured by Kd)
• The drug molecule composed from carbon
skeleton (which give the steric shape) and
functional groups (binding groups) which
specifically binds to receptor.
Cellular location of receptor molecules
1.
Cell membrane
2.
Cytoplasm
3.
Nuclear membrane
4.
Nucleus
Ligand molecules
• Not all small drug molecules act through specific receptors.
• Some small drug molecules interacts non-specifically with lipopolysaccharides, carbohydrates
and DNA
For example: some group of compound used as narcotics or anaesthetics, the pharmacological effect is
mainly related to physical rather than chemical properties.
In other word, Those group of compounds
1.
2.
Contain diverse chemical groups
Their pharmacological effect is attained rapidly and disappear rapidly when the supply is removed (i.e.
equilibrium is exist between the external phase and biophase)
• Other small drug molecules interacts specifically to protein (most common) or DNA/RNA (less
common). Why?
For example: most the available drugs. Those group of compounds
1. Contain specific scaffold (molecular frame or molecular backbone) in common to drugs act on same receptor
2. Their pharmacological effect is attained rapidly and disappear slowly when the supply is removed (i.e.
equilibrium is exist between the free and receptor bound form)
Specific and non-specific binding of ligands
Drug molecule
act through
specific receptor
Binds to specific receptor
Like enzyme (agonists/antagonists)
Cell-membrane receptors (agonists/antagonists)
receptor
Nuclear
receptor (agonists/antagonists)
receptor
Affects membrane solubility
Like some anesthetics and antifungal agents
Binds to DNA
Like some anticancer agents
Drug molecule
act through nonspecific receptor
Binds to proteins
Like free radicals and some poisons
Cell
Specific and non-specific binding of ligands
• On the basis of the mode of action, drugs are divided into two categories
1.
Drugs act through non-specific receptors
+
2.
Drugs act through specific receptors
+
𝐾𝑜𝑛
𝐾𝑜𝑓𝑓
𝐾𝑜𝑛
𝐾𝑜𝑓𝑓
• Differences between structurally nonspecific drugs and structurally specific drugs
Ligands act through non-specific binding
Ligands act through specific binding
1
Their biological action is directly related to affinity to Their biological action is directly related to affinity to
non receptor (measured by Kd)
receptor (measured by Kd)
2
High doses are needed for biological activities
They are effective in low concentrations
3
Chemical structures are different, but they produce
similar biological responses
They have some structural characteristics in common to
produce the biological Response
4
Slight modifications in their chemical structure do
not result in pronounced changes in biological
action
Slight modifications in their chemical structure may
result in substantial changes in biological activity
5
More toxic
Less toxic
Example of drugs acting through non-specific receptors
• Amphotericin B and Miltefosin are
example of drugs act by non-specific
binding
• Drugs have less similar structures
• Both drugs used as antifungal agents.
• Both drugs disturb the phospholipid
membrane integrity by acting as
surface-active agents.
• Toxic when used systematically
Miltefosin
Example of drugs acting through non-specific receptors (Cont.)
TUNNEL
Polar tunnel formed
Escape route for ions
• Action of amphotericin B (antifungal agent)
HO2C
OH
OH CO2H
Sugar
Sugar
• Builds tunnels through membrane and drains cell
Hydrophilic
OH
Hydrophilic
O
HO
O
HOOC
OH
OH
OH
OH
OH
O
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
HO
OH
H
Hydrophilic
Me
Me
O
HO
CELL
MEMBRANE
Me
Me
O
OH
Hydrophobic region
NH2 HO
HO
Sugar
HO2C
Sugar
OH
OH
CO2H
Example of drugs acting through non-specific receptors (Cont.)
• Some anesthetic agents are also belong to the group of non-specific acting drugs.Substances like
alkanes, alkenes, alkynes, ketones, amides, chlorinated hydro-carbons, ethers and alcohols display
narcotic activity which is directly proportional to the partition coefficient of each individual
substances.
Na+ channel
• the interaction of the anesthetic molecules with a hydrophobic portion of the nerve membrane
caused a distortion of the nerve membrane near the channels that conducted Na+, those that
mediated the fast action potentials and neuronal cell firing.
Example of drugs acting through non-specific receptors (Cont.)
• Intercalating agents are group of
anticancer agents which act by
non-specific binding .
• The intercalating agents have no
specific structures, except having
planner aromatic system and a
polar amino group
PO4-
PO4-
PO4-
PO4-
+NR4
PO4-
PO4-
Case study for compounds act through non-specific receptors:
• The correlation between lipid solubility and anesthesia measured by tadpole motility.
Compound
Partition coefficient
(n-Octanol/Water)
Required cnoc. to
immobilize tadpole
Calcul. Depressant
Conc in cellular lipids
1
Thymol ‫من الزعتر‬
950
0.000047 moles
0.045
2
Valeramide-OM
0.03
0.07 mol2
0.021
3
2-nitro aniline
14
0025 moles
0.035
Thymol
Valeramide-OM
2-nitro aniline
Specific drug receptors
• The drug can bind to specific receptor (target) to form complex.
• The drug-receptor complex will lead the receptor function to be
affected in different ways depending on type of receptor and
(ligand):
• The specific drug receptors can be classified into:
A) Machine receptors: like all enzymes
1.
2.
B)
Active (Substrate)
Inactive (Inhibitor)
Switch receptors: like transmembranal proteins (sensors, ion
channels) and enzymes contain allosteric switches
1.
2.
3.
4.
5.
6.
OFF (Inhibitor / antagonist)
ON (Potentiator / agonist)
OFF with partial ON (partial antagonist)
ON with partial OFF (partial agonist)
Partial OFF and cannot be completely OFF by antagonist (inverse
antagonist)
Partial ON and cannot be completely ON by agonist (inverse
agonist)
𝐾𝑜𝑛
+
𝐾𝑜𝑓𝑓
Pharmacological
effect
Drug
receptor
Diagram represent
most known specific
receptors
Partial OFF difficult to be
completely OFF
(Inverse antagonist)
Partial ON difficult to be
completely ON
(Inverse agonist)
Partial OFF
(Partial antagonist)
Partial ON
(Partial agonist)
Switch
Like GPCR e.g.
adrenergic receptors,
etc.
ON
(agonist)
OFF
(antagonist)
Cell membrane
Self
controlled
Machine
Substrate
Substrate
Product
Drug
Like enzymes
with allosteric
site. e.g.
Inhibitor
Drug
Enzyme
Machine
Like most enzymes
e.g. acetylcholine
estrase, peptidase,
etc.
• Even switch receptors are directly or
indirectly regulates enzymatic
reactions.
• Therefore, enzymes are considered
directly or indirectly the most
important type of specific drug
receptors.
• Each enzyme catalyze specific set of
biochemical reactions, therefore,
inhibition of specific enzyme lead to
specific set of pharmacological effects.
+
S
E
ES
Reversible
interaction
+
P
E
ES++
You can view energy in different ways
• This is how we can correlate interaction energy with Kd
+
The change in energy
‫مقدار التغير في الطاقة‬
∆𝑯 − 𝑻∆𝑺 = ∆𝑮 = −𝑹𝑻 𝒍𝒏𝑲𝒅




-ve for spontaneous rxn
+ve for nonspontaneous rxn
Zero at equilibrium (i.e. at Kd=1)
Path independent (depend on starting and
end states)
 Gives information on rxn spontaneousity
 Gives NO information on rxn rate
𝐾𝑜𝑛
𝐾𝑜𝑓𝑓
• Therefore, enzy
most important
• Each enzyme ca
biochemical rea
inhibition of sp
specific set of p
+
S
E
ES
Reversible
interaction
+
P
E
ES++
Free energy diagram for the reaction pathway of a
chemical reaction, and the same reaction catalyzed by
an enzyme. Note the significant reduction in activation
energy (the vertical distance between the reactant
state and the transition state) achieved by the enzymecatalyzed reaction
Principles of enzyme function
E+S
• 𝐾𝑑 =
𝐾𝑠
ES
𝐾𝑐𝑎𝑡
𝐾𝑜𝑓𝑓
𝐾𝑜𝑛
• ∆𝐺 = −𝑅𝑇 ln 𝐾𝑑
• ∆𝐺𝐸𝑆 = −𝑅𝑇 ln 𝐾𝑠 (Energy to form ES)
• ∆𝐺𝐾𝑐𝑎𝑡 = −𝑅𝑇 ln 𝐾𝑐𝑎𝑡 − − 𝑅𝑇 ln
• ∆𝐺𝐸𝑆++ = −𝑅𝑇 ln
𝐾𝑐𝑎𝑡
𝐾𝑠
− − 𝑅𝑇 ln
𝐾𝐵 𝑇
ℎ
𝐾𝐵 𝑇
ℎ
Drive of
random motion
ES++
~1
EP
𝐾𝑝
E+P
Principles of enzyme function
• The reason for the slow rates of most reactions involving organic
substances is the high activation energy that the reacting
molecules have to reach before they can react.
• A catalyst creates a new pathway for the reaction. When all of the
transition states arising have a lower activation energy than that
of the uncatalyzed reaction, the reaction will proceed more
rapidly along the alternative pathway, even when the number of
intermediates is greater.
• Catalysts—including enzymes—are in principle not capable of
altering the equilibrium state of the catalyzed reaction.
• The often-heard statement that “a catalyst reduces the activation
energy of a reaction” is not strictly correct, since a completely
different reaction takes place in the presence of a catalyst than in
uncatalyzed conditions.
Koolman, Jan, et al. Color atlas of biochemistry. Vol. 2. Stuttgart: Thieme, 2005.
How uncatalyzed reactions proceed
• The reaction A + B C + D is used as an
example. In solution, reactants A and B are
surrounded by a shell of water molecules (the
hydration shell), and they move in random
directions due to thermal agitation. They can
only react with each other if they collide in a
favorable orientation. This is not very
probable, and therefore only occurs rarely.
• Before conversion into the products C + D, the
collision complex A-B has to pass through a
transition state, the formation of which
usually requires a large amount of activation
energy, Ea. Since only a few A–B complexes
can produce this amount of energy, a
productive transition state arises even less
often than a collision complex.
• In solution, a large proportion of the activation
energy is required for the removal of the
hydration shells between A and B. However,
charge displacements and other chemical
processes within the reactants also play a role.
• As a result of these limitations, conversion
only happens occasionally in the absence of a
catalyst, and the reaction rate v is low,
evenwhen the reaction is thermodynamically
possible—i. e., when ΔG < 0.
How catalyzed reactions proceed
•
Enzymes are able to bind the reactants (their
substrates) specifically at the active center. In the
process, the substrates are oriented in relation to
each other in such a way that they take on the
optimal orientation for the formation of the
transition state (1–3).
•
The proximity and orientation of the substrates
therefore strongly increase the likelihood that
productive A–B complexes will arise. In addition,
binding of the substrates results in removal of
their hydration shells. As a result of the exclusion
of water, very different conditions apply in the
active center of the enzyme during catalysis than
in solution (3–5).
•
A third important factor is the stabilization of the
transition state as a result of interactions
between the amino acid residues of the protein
and the substrate (4). This further reduces the
activation energy needed to create the transition
state. Many enzymes also take up groups from the
substrates or transfer them to the substrates
during catalysis..
•
Proton transfers are particularly common. This
acid–base catalysis by enzymes is much more
effective than the exchange of protons between
acids and bases in solution. In many cases,
chemical groups are temporarily bound covalently
to the amino acid residues of the enzyme or to
coenzymes during the catalytic cycle. This effect is
referred to as covalent catalysis.
How enzyme catalyzes the reaction
• Although it is difficult to provide
quantitative estimates of the
contributions made by individual
catalytic effects, it is now thought
that the enzyme’s stabilization of
the transition state is the most
important factor.
• It is not tight binding of the
substrate that is important,
therefore—this would increase the
activation energy required by the
reaction, rather than reducing it—
but rather the binding of the
transition state.
• This conclusion is supported by the
very high affinity of many enzymes
for analogues of the transition
state. A simple mechanical analogy
may help clarify this (right). To
transfer the metal balls (the
reactants) from location EA (the
substrate state) via the higherenergy transition state to EP (the
product state), the magnet (the
catalyst) has to be orientated in
such a way that its attractive force
acts on the transition state
(bottom) rather than on EA (top).
What is
•
•
•
•
Enzymes are proteins that function as catalyst for chemical reactions.
Chemical reactions catalyzed by enzymes are called “biochemical reactions”.
Enzymes harbor a site which can bind the reactant (substrate) and convert it into product.
Enzymes do:
-
Accelerate rate of chemical reactions
Act on specific molecules of substrates and products
Induce strains and perturbations that convert the substrate into transition state structure.
Bind to substrate in thermodynamically favorable way
Do catalyze reaction by regio- and stereo- (enatiomerically) selective way
• The enzyme active site:
-
Is small in size
Has 3D shape
Interacts with substrates by initial non-covalent interactions
Present in cleft or cavity
How enzyme catalyzes the reaction (Cont.)
• Enzyme catalyzes reaction by:
1.
Binding substrate molecule through reversible non-covalnet interactions
2.
Shielding substrate molecules from bulk solvent and creating a localized dielectric environment
that helps reduce the activation barrier to reaction
3.
Binding substrate(s) in specific orientation that aligns molecular orbitals on the substrate
molecule(s) and reactive groups within the enzyme active site for optimal bond distortion
(orbital steering) as required by the chemical transformation of catalysis.
4.
Stabilize the steered molecular orbitals
5.
May temporarily binds to a chemical group of one of the substrates before transferring it to the
other.
Common features for enzyme active site
• Some of the salient features of active site structure that relate to enzyme catalysis and ligand (e.g.,
inhibitor) interactions include:
1. The active site of an enzyme is small relative to the total volume of the enzyme.
2. The active site is three-dimensional—that is, amino acids and cofactors in the active site are held in a
precise arrangement with respect to one another and with respect to the structure of the substrate
molecule. This active site three-dimensional structure is formed as a result of the overall tertiary
structure of the protein.
3. In most cases the initial interactions between the enzyme and the substrate molecule (i.e., the initial
binding event) are noncovalent, making use of hydrogen bonding, electrostatic, hydrophobic
interactions, and van der Waals forces to effect binding.
4. The active site of enzymes usually are located in clefts and crevices in the protein. This design
effectively excludes bulk solvent (water), which would otherwise reduce the catalytic activity of the
enzyme. In other words, the substrate molecule is desolvated upon binding, and shielded from bulk
solvent in the enzyme active site. Solvation by water is replaced by specific interactions with the
protein.
5. The specificity of substrate utilization depends on the well-defined arrangement of atoms in the
enzyme active site that in some way complements the structure of the substrate molecule.
• Two types of amino acids available inside enzyme active site:
• Catalytic amino acids: directly or indirectly participate in enzymesubstrate interactions
• Non-catalytic amino acids:
• Complete the construction of active site pocket
• Help shaping tunnels and opening to active site, especially when the pocket
is deep inside.
• Might play role in binding (anchoring) substrate to bring it close to catalytic
amino acids.
• Evacuate the site from water  ↓dielectric constant  ↑interaction
Inhibitor interaction MAY or MAY NOT be similar to substrate interaction
Methotrexate
(inhibitor)
Dihydrofolate
(Substrate)
Interactions of the dihydrofolate reductase active site with the inhibitor methotrexate (left) and the substrate dihydrofolate (right) in similar manner.
How to inhibit truck movement
• To inhibit a truck movement, you can either:
-
Destroy the truck
Destroy the engine
Remove the spark plug
Cover the spark plug with grease √
• According to easiest method to stop a truck, there is no need to fully
occupy the enzyme active site in order to stop enzyme function. You can
simply cover part of the active site by a compound.
• Effective small molecule inhibitors of ACE, such as the antihypertensive
drugs captopril and enalapril, function by chelating the critical zinc atom
and thus disrupt a critical catalytic component of the enzyme’s active site
without the need to fill the entire volume of the angiotensin I binding site.
Angiotensin I
Captopril
(Big substrate)
(small inhibitor)
Degree of specificity
• Although they are classified as specific receptors, the degree
of specificity is variable.
• According to degree of specificity to substrates, enzymes can
be classified into:
1. Very specific: in which only specific substrate can fit the
active site. E.g. carboxyestrase, COMT, Acetylcholine
estrase.
2.
Not very specific (Broad): in which a set of specific
substrates can fit the active site. E.g. peptidases,
cytochrome P450, glutathione-S-transferase, and other
xenobiotic metabolizing enzymes.
Acetylcholine estrase binds acetylcholine (2HA4)
• It is the shape and amino acid composition of the active site
which provides the specificity.
• Frequently less specific enzymes have wide active site.
Glutathione-S-transferase binds GS-CDNB (1XWK)
Specificity parameters
1.
Regio-specificity
• Enzymes are regio-specific i.e. catalyse reaction on specific group at specific position even if
another identical group is available elsewhere.
• Example:
• Catecholamine-O-Methyl Transferase (COMT): only methylates hydroxyl group that is meta to
amino ethylene group
COMT
SAM
Specificity parameters (Cont.)
2. Stereo-specificity
• Enzymes are stereo-specific i.e. bind to specific isomer
or enantiomer of substrate (as well as inhibitor).
• Therefore, only single isomer of drug is usually active.
• Examples:
•
•
•
•
R isomer of Adrenaline is much more active than S
R isomer of Salbutamol is much more active than S
S-methacoline is more active than R-methacoline
S-ibuprofen is more active than R-ibuprofen
Specificity parameters (Cont.)
• For example, the levorotatory form
of epinephrine is one of the
principal hormones secreted by the
adrenal medulla.
• When synthetic epinephrine is given
to a patient, the (-) form has the
same stimulating effect as the
natural hormone. The form (+) lacks
this effect and is mildly toxic
Classification of amino acids
Types of enzyme inhibitors
• Enzyme can be inhibited by three types of molecules
1.
Competitive inhibitors:: Molecules bind at the active site. Usually the molecules are structural
analogues to the substrate and can do compete the substrate at the active site
2.
Uncompetitive inhibitors: Molecules bind at the allosteric (switch) site. Usually the molecules
are not similar to the substrate and do not compete the substrate at the active site.
3.
Non-competitive inhibitors: Molecules bind at both active and allosteric sites. Usually the
molecules show partial competition for the substrate at the active site.
• For an enzyme inhibitor to be used as drug it should:
1.
The enzyme catalyases a biochemical reaction which lead to disease
2.
Enzyme inhibitor be specific to the particular enzyme with lower affinity to other enzymes
(𝐾𝑖 < 𝐾𝑠𝑖𝑑𝑒 ).
Example of enzyme inhibitors used as drugs
• Enzyme inhibitor
1. Aminotransferase
- Function: deactivates GABA (resting neurotransmitter)
- Inhibition: ↑ GABA  anticonvulsant effect
2.
Xanthine oxidase
- function: oxidize xanthine to uric acid (accumulated in joints)
- Inhibition: ↓uric acid production  treatment of gout
3.
Beta-lactamase
- function: destroy beta-lactam of penicillin (provide bacterial resistance to penicillin)
- Inhibition: ↓ destruction of penicillin  improve the spectrum of penicillin
4.
Dihydropteroate synthase and folate reductase
- function: both enzymes act in the same pathway for synthesis of folic acid in bacterial cell
- Inhibition: ↓ biosynthesis of folic acid  stop replication of bacterial cell
- This is an example of “synergism” in which if two types of inhibitors are used to inhibit two different
enzymes involved in a single pathway. The benefit of synergism is higher activity with lower doses of
each inhibitor
2. Switch receptors
• Some of the switch receptors are very rapid (e.g. those involved
in synaptic transmission operating within milliseconds), and
others very slow (e.g. hormone receptors operate after hours
and days.
• Switch receptors can be classified into:
1.
2.
3.
4.
Ligand-gated ion channels
G-protein-coupled receptors
Switch
Kinase-linked receptors
Cell membrane
Nuclear receptors
Components of switch receptors
1. Ligand-binding domain
Extracellular to allow easy access for ligands.
Strong affinity for specific ligands - allows
different ligands that bind to the same
receptor to evoke particular cellular
responses.
2. Transmembrane domain
Contains a series of hydrophobic amino
acids. Tethers the receptor to the cell
membrane.
Enzyme
3. Cytosolic "active" enzyme domain
Either intrinsic to the receptor or tightly
bound via the cytosolic domain.
The majority are kinases; they phosphorylate
specific threonine, serine, and tyrosine
amino acid residues (THR,S,TY = THIRSTY)
Signal transduction between switch and enzyme
• Such processes take place in as little as a millisecond or as long as a few seconds. Slower
processes are rarely referred to as signal transduction
1.
it enables extracellular molecules to affect cellular function without entering the intracellular
environment.
2.
Second, several different signals can affect one another by facilitating or inhibiting the
activation of regulatory enzymatic proteins via common or opposing metabolic pathways.
3.
Third, via the activation of enzymes and the production of second messengers (e.g., cAMP,
• diacylglycerol [DAG], and IP3), an initially weak signal can be amplifi ed many times, and its
uration prolonged, to produce a robust cellular response.
Types of switch receptors
1. Ligand-gated ion channels:
• The ligand-gated ion channels are also known as ionotropic
receptors.
• These are membrane proteins with a similar structure to other
ion channels, but incorporating a ligand-binding site (switch
receptor), usually in an extracellular domain.
• Typically, these are the receptors on which fast
neurotransmitters act.
• Examples: nicotinic acetylcholine receptor, GABAA receptor,
and glutamate receptor of N-methyl-D-aspartic acid (NMDA).
• Textbook of Medicinal Chemistry Vol I 1st Edition Authors: V Alagarsamy
Types of switch receptors (Cont.)
2. G-protein-coupled receptors (GPCR)
• GPCR is also called metabotropic receptors or seven-trans
membrane spanning receptors that act through a second
messenger, which elicits an action.
• Second messengers usually are cyclic adenosine
monophosphate (cAMP) and inositol trisphosphate (IP3)
produced by cytoplasmic enzymes linked to the receptor.
• Examples: muscarnic receptors, beta adrenergic receptors,
serotonin receptors and opioid receptors.
• Textbook of Medicinal Chemistry Vol I 1st Edition Authors: V Alagarsamy
Types of switch receptors (Cont.)
3. Kinase-linked or enzyme-linked receptors:
• These constitute extracellular ligand-binding
domain that is
• linked to an intracellular domain by a single
transmembrane helix. In many cases, the
intracellular domain is enzymatic in nature.
Examples include receptors for insulin and
various cytokines.
When the ligand binds a protein kinase-associated
receptors, the kinase activity is stimulated and a
cascade of phosphorylation transmits the signal
• Textbook of Medicinal Chemistry Vol I 1st Edition Authors: V Alagarsamy
Types of switch receptors (Cont.)
4. Nuclear receptors:
• The nuclear receptors regulate the gene
transcriptions, are located in the cytosol, and
migrate to the nuclear compartment when a ligand
is present.
• The receptor protein is inherently capable of binding
to specific genes. These include the receptors of
glucocorticoids and thyroid hormone.
Enzymes and switches inhibitors
• As mentioned previously, drugs may bind to switch or enzyme (mainly
through reversible non-covalent interaction).
• Drugs affecting switch function are ranged from antagonist, partial
antagonist, inverse antagonist, inverse agonist, partial agonist, and
agonist)
Non-competitive
• Drugs acting on enzyme are substrates or inhibitors.
• What will be the case if enzyme in cytoplasm carries its switch?
Switch
• Drugs acting on enzyme that has switch (allosteric site) are range from
competitive inhibitors (acting on active site) or uncompetitive inhibitor
(acting on allosteric site), or mixed mode inhibitor (acting on both sites).
• Mixed mode inhibitors are called Non-competitive inhibitors
Enzyme
Competitive
Uncompetitive