Know the following types of molecular drug targets and can explain their
characteristics:
G-coupled protein receptor, receptor with enzyme activity (kinase receptor),
intracellular
receptor, transporter, and ion channel.
G-Protein Coupled Receptors (GPCRs)
o Structure
Membrane-bound receptors with seven transmembrane
domains
o Mechanism
Ligand binds to GPCR on extracellular side activation of
associated G-protein on intracellular side initiation of
cascade of intracellular signaling pathways
o Function
Regulate wide variety of physiological processes
Neurotransmission
Hormone responses
Immune responses
Sensory perception
o Drug Targeting
One of most common drug targets involvement in diverse
signaling pathways
Targeting GCPRs can act as agonists or antagonists.
Enhancing or inhibiting receptor’s signal
o Examples
β-adrenergic receptors
Dopamine receptors
Opioid receptors
Receptors with Enzyme Activity (Kinase Receptors)
o Structure
Membrane bound
Extracellular ligand-binding domain
Single transmembrane helix
Intracellular enzymatic domain
o Mechanism
Ligand binding to receptor’s extracellular domain activation
of intracellular kinase domain phosphorylation of specific
tyrosine, serine, or threonine residues on target proteins
initiation of downstream signaling cascades
o Function
Cell growth
Differentiation
Metabolism
Survival
o Drug Targeting
Many anticancer drugs target kinase receptors, especially
overactive or mutated in cancer cells
o Examples
Epidermal Growth Factor Receptor (EGFR)
Insulin receptor
1
, MVD
Vascular Endothelial Growth Factor Receptor (VEGFR)
Intracellular Receptors (Nuclear Receptors)
o Structure
Inside cell, in cytoplasm or nucleus
Distinct domains for ligand binding, DNA binding, and
transactivation
o Mechanism
Intracellular receptors bind to lipophilic molecules (e.g.,
steroid hormones), diffuse through cell membrane
receptors dimerize and translocate to nucleus act as
transcription factors to regulate gene expression
o Function
Regulate gene expression
Affect processes like metabolism, inflammation, and cellular
differentiation
o Drug Targeting
Often used as targets in hormone-related diseases
Estrogen receptor modulators in breast cancer
Glucocorticoids for anti-inflammatory effects
o Examples
Estrogen receptor
Androgen receptor
Glucocorticoid receptor
Transporters
o Structure
Membrane proteins
Multiple transmembrane
Form a channel or series of binding sites
o Mechanism
Transporters move ions, small molecules, or macromolecules
across cell membranes, often against concentration gradients
Movement can be passive or active
o Drug Targeting
Drugs targeting transporters can either inhibit or enhance
transport functions
SSRI block reuptake of serotonin
o Examples
Sodium-glucose cotransporter (SGLT)
Serotonin transporter (SERT)
Dopamine transporter (DAT)
Ion Channels
o Structure
Membrane-bound proteins form pores across cell
membranes allows for ion passage
o Mechanism
Can be voltage-, ligand-, or mechanically gated
o Function
Regulate flow of ions across cell membrane
Crucial for electrical signaling in neurons, muscle contraction,
and cellular homeostasis
o Drug Targeting
Used in treating conditions like epilepsy, arrythmias, and pain
Modulate channel activity by blocking or enhancing ion flow
Understand the concept of binding and can apply the terms occupancy, affinity,
Kd,
agonism, antagonism, and competitive vs. non-competitive in the context of
binding.
Binding Basics
o Binding
Interaction between ligand and target
Results in biological effect
Key Term in Binding
o Occupancy
Proportion of target receptors that are occupied by a ligand at
any given time
Higher occupancy stronger biological response
Effects plateaus one most receptors are occupied!
o Affinity
Measure of how strongly a ligand binds to its receptor
High-affinity ligands bind more tightly and are more likely to
remain bound than low-affinity ligands
Inversely related to dissociation constant (Kd)
o Dissociation Constant (Kd)
Concentration of a ligand at which half of the available
receptors are occupied
Lower Kd higher affinity less ligand needed to occupy
50% of the receptors
Kd is a fundamental parameter, reflecting the equilibrium
between bound and unbound ligand at the receptor
Types of Ligand: Agonism an Antagonism
o Agonist
Ligand binds to receptor activation biological response
Full agonist: produce maximum response possible
Partial agonist: produce lower response, even when all
receptors are occupied
o Antagonist
Ligand binds to receptor no activation blocking or
dampening action of agonist
Important in preventing or reducing unwanted biological
responses
Competitive vs. Non-Competitive Binding
o Competitive Antagonism
Competitive antagonist binds to the same site on the receptor
as the agonist direct competition
Enough agonist present can overcome antagonist’s effect
Increases apparent Kd for the agonist, BUT maximum possible
response can still be achieved, if enough agonist is present
o Non-Competitive Antagonism
Non-competitive antagonists bind to different site than
agonist (allosteric site) change receptor’s shape or function
prevents agonist from fully activating receptor
Understand the concept of response and can apply the terms agonist, partial
agonist,
antagonist, inverse agonist, efficacy, potency, EC50, Emax, specificity,
selectivity, and dose response relationships (including therapeutic index).
Concept of Response
o Response
Biological effect produced when a drug binds to its target
Response can vary in intensity
Types of Drugs Based on Response
o Agonist
Binding to receptor activation biological response
Full agonist can produce maximum response possible
o Partial Agonist
Binding to receptor activation weaker response
Lowers overall response
Can act as competitive inhibitors when combined with full
agonist
o Antagonist
Binding to receptor no activation blocking of receptor
No intrinsic activity, but crucial in reducing or preventing
undesired effects caused by agonists
o Inverse Agonist
Binds to same receptor as agonist production of opposite
effect decreased receptor’s activity below baseline level
Response Characteristics
o Efficacy (Intrinsic Activity)
Describes a drug’s ability to produce maximal biological
response
Agonist: high efficacy
Antagonist: zero efficacy
Partial agonist: moderate efficacy
o Potency
Amount of drug needed to produce a specific effect
Higher potency response at lower dose low EC50
o EC50
Concentration (dose) that produced 50% of maximal effect
Lower EC50 higher potency
o Emax
Maximum effect than can be achieved with a drug, regardless
of dose
Efficacy is tied to Emax: higher Emax stronger responses at
saturation
Specificity & Selectivity
o Specificity
Drug’s ability to bind only to a specific target fewer off-
target effects
Highly specific drugs target a single receptor or protein
o Selectivity
Drug’s preference for one receptor or target over others, even
if it can bind to multiple receptors at different affinities
4
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