Exam 1 Flashcards
What is drug discovery
Early sources of drugs
-Natural products derived from plants
Based on observation of medicinal properties (discover)
What is drug invention
Modern approach is a process (inventive)
Chemical synthesis, experimentation and optimization
What is rational drug design
Starting from a known molecule and optimizing it through synthsis to improve its potency, selectivity, stability
What is screening
Random process
-identify a target
-develop a screen that identify active compound
-test large library of compounds to get a hit
-modify hits to get a lead molecule
What are screening library approach refined through
Combinatorial chemistry
Increased chemical diversity of compound libraries
High-throughput screening (well plate test)
Virtual screening (big chemical databases)
Small vs large molecules
In the past many were small, but now recombinant DNA technology permitted development of large molecules
Targets of drug action critical questions to ask
-can one find a drug that will have the desired effect against its target
-does modulation of the target protein affect the course of disease
-does this project make sense economically
What are druggable targets
Does it have known binding sites
-Do other small ligands interact with target
-What type of molecules interact (smaller are ideal)
Are binding sites extracellular or intracellular
-Extracellular are better because they don’t have to go through membranes
Valid drug target
Is the target critical for disease process (or normal function)
-What happens if the target is disrupted
-Redundancy of biological systems
-Adaption to presence of drugs
Economically viable targets
Biotech start-ups and university spin-offs
-Funded by small investors or grants
Big Pharma (large companies)
-Well funded, lots of resources
Private foundations and non-profits
-Special interests
Federal Agencies (NIH, FDA)
-Help support university and small business efforts
-Support rare diseases (ophans)
Preclinical Research
Medicinal Chemistry
-synthesis of novel compounds
Pharmacology
-Measure affinity, selectivity, activity
-Pharmacokinetic properties (ADME)
Pharmaceutics
-Pharmaceutical properties (stability, solubility, formulation)
Toxicology
-safety
Preclinical safety data required
Acute toxicity studies
-several doses
-at least two species (one non-rodent)
Chronic tox studies
-period related to extent of proposed human use
-two species (one non-rodent)
Genotoxicity, cardiotoxicity, respiratory safety, other systems
-In vitro
-In vito
What is in the investigational new drug application (IND)
Chemistry, manufacturing (API)
Pharmacological, pharmokinetics, tox data
Human study rational
Protocol plan
How long does the FDA have to approve the IND application
30 days
If no contact before then trails can start
Role of US food and drug administration
Responsible for protecting public health by assuring safety, efficiency, and security of drugs
What were some setbacks of the pure food and drug act
No restrictions on what was in the medications
Needed to implement tox testing
Resulted in NDA (new drug application)
Food drug and cosmetic act
Kefauver-Harris amendments
Ads that have side effects listed
What is an IRB (institutional review board)
It is a board at a university to approve trials
they review protocols, address privacy concerns, requires informed consent to participate in clinical trials
What do phase 1 and 2 do in clinical trials
Phase I: 10-100 healthy volunteers, emphasis on safety
Phase 2: 50 -500 people with disease, focus on efficacy
What are phase 3 and 4 in clinical trials
Phase 3: 200 - 2,000 patients, full drug approval
Phase 4: 10,000+ patients
What are the seven ethical principles for conducting clinical trails
social and clinical value
scientific validity
fair selection of subjects
informed consent
favorable risk-benefit ratio
independent review
respect for potential and enrolled subjects
What is the importance of hypothesis testing for clinical trials
identify primary endpoint for assessing outcomes
surrogate endpoints
biomarkers
What is the importance of sample size for clinical trials
small size for initial studies of safety
large size for studies of efficacy
What is the belmont report outlines ethical framework for studies with human subjects
respect for persons
beneficence
justice
What are biomarkers
a characteristic that is measured as an indication of a physiological process or pathological state
What is type for biomarkers
target
mechanism
outcome
What is linkage to efficacy or outcome for biomarkers
low - no consistent linage
medium - some information
high - reproducibility demonstrated
Why is it important for biomarkers to have predefined criteria and qualification of biomarkers
predefined criteria: similar to considerations about primary clinical endpoints
qualification of biomarkers: assay or measure reliably established and reflects outcome or safety
What does ADME stand for in pharmacokinetics
Absorption
Distribution
Metabolism
Elimination
What properties determine the nature of drug action of pharmacodynamics
Binding and activity at therapeutic target
Toxicity (bind and activity at other targets)
What is pharmacokinetics
the study of biochemcial and physiological effects of drugs and their mechanism of action
What are drug targets
Cell surface
Intracellular
Nucleus
DNA
Protein
What are chemical messengers
Cell to cell communication
-Hormones (distal)
-Neurotransmitters (local)
Modulate activity at receptor represents important target for therapeutic intervention
How are receptors named
For endogenous compound
Cholinergic receptors are activated by acetylcholine
Muscarinic - GPCR
Nicotinic - ligand gated
Called ________ receptors when endogenous compound is unknown
orphan
Agonists
Activates receptors
-produces physiological responses (full vs partial)
-Endogenous compounds are agonists (acetylcholine)
-Synthetic compounds or natural products may be agonists
Antagonists
Inhibit physiological responses produced by agonists
-shift agonist dose response to right in parallel manner
Inverse agonists
Produce opposite effect of agonist
-may inhibit agonist response
Allosteric Ligand
modify agonist activity
bind to site outside agonist binding site (orthosteric site)
Orthosteric site vs Allosteric site
Orthosteric: site for endogenous ligand, competitive inhibitor, highly conserved amino acid residue
Allosteric: modulate binding to orthosteric site, may activate or inhibit receptors, less highly conserved
Drug affinity and intrinstic activity related to chemical structure
-small changes in structure may lead to large changes in pharmacological properties
-stereoselectivity
-pharmacophore (functional groups, chem properties)
How has drugs interaction with receptors been enhanced by several recent developments
-Molecular modeling of drug molecules combined with structure activity relationship studies
-Site-directed mutagenesis
-Structural data for receptors
G protein coupled receptors
-Mediate slow onset, long duration responses
-Target for many best-selling drugs
What does Gi, Gs, Gq, G(olf), Gt do
Gi: inhibits adenylyl cyclase
Gs: stimulates adenylyl cyclase
Gq: stimulates phospholopase C
G(olf): olfactory G protein mediates olfactory sensation
Gt: transducen mediates sensitivity to light
What do odd and even muscarinic receptors do
odd: activate Gq (promote phosphoinositide metabolism)
even: activate Gi/o (inhibit adenylyl cylase, decrease cAMP)
What do ligand-gated channels do
regulate ion flow in response to extracellular signals
can be excitatory or inhibitory depending on ion flow
What do nicotinic receptors do
mediate fast-onset, short duration responses to acetylcholine
What are GABA receptors
predominant inhibitory receptor in the CNS
How long are patents good for
20 years about date filed
(5 years on market)
Generic vs brand name
generic: assigned by USAN council
brand: assigned by manufacturer
Tyrosine kinases and growth hormones activate ________ signals that alter cellular function
intracellular
Nuclear receptors regulate gene ________ and __________ of proteins
transcription and translation
What is quantification
interaction between drugs and receptors
*important for understanding relationship between dose and response of drug
What are dose-response curves
Permit a measure of receptor binding or activity as a function of drug concentration
What is KD and EC50
KD: affinity
EC50: potency
What is B(max) and S(max)
B(max): binding
S(max): activity
What is the difference between linear and log plots
linear is closer together and can not see the curve while log you can
Stats for mean values are converted to what
convert to log units then calculate mean then convert back
When KD is low it indicates ______ affinity
high affinity
(low concentrations are needed to occupy half the receptors)
What are competitive antagonists
Indicated when agonist and antagonist compete for same binding site on receptor
-shift to right
What are irreversible antagonists
Antagonist dissociates slowly from receptor
*agonist can not overcome presence of antagonist
-shift to right
Increasing concentrations of ______ cannot fully overcome the effects of allosteric inhibitors
agonsists
Endogenous ligands bind to what sites
orthosteric sites
Orthosteric binding sites are more highly conserved than _________ sites
allosteric
Allosteric ligands can enhance or inhibit activity of ________
agonists
Allosteric ligands can directly activate or inhibit ________
receptors
Positive allosteric modulators (PAMs) can enhance agonist potency (PAM __) or agonist efficacy (PAM __)
potency: X
efficacy: Y
