Pharmacogenomics Flashcards
What is a drug?
A medicine or other substance which has a physiological effect when ingested or otherwisw introduced into the body
What is a drug target?
It can be a protein, cell or organ affected by a specific drug
Can impact human host, bacteria, or viruses
What are the characteristics of a “good” drug?
- Potent
- Specific
What is the reason for drug failures in the drug development process?
Flawed biological hypothesis (wrong target chosen)
- often due to a lack of understanding of the fundamental molecular mechanisms
What are some challenges in drug development?
- Identify all the protein/genes that can be a potential target
- Identify all compunds that can be used as drugs
- Confirmation that a compund inhibits the intended target
- Identification of undesirable secondary effects
How are potential drug targets identified by drug manufacturers/researchers?
- Data-mining (using existing literature to find associations between genes and disease)
- Genetic/Genomic approaches (compare protein and transcriptome arrays)
- in vitro approaches
How are drug targets validated?
- Does target knock-out have the desired effects?
- Where in the body is the gene expressed, does it vary with age or sex
- Are there alternate pathways available (need to target chokepoints)
- Can we execute a drug-discovery program
- Is the target druggable (good access and afinity due to pocket morphology)
- Is selectivity necessary/acheivable
- Is there a suitable animal model system
What are chokepoints in drug targets?
Drugs should target the step that has no alternate pathways to the substance you want to modulate
What is the difference between forward and reverse chemical genetics (chemogenomic screens)?
Forward chemical genetics: chemical identified first and given to target, see which chemical worked, then check how it is causing effect
Reverse chemical genetics: Identfiy target first, then visit compound library to find chemical that will bind to target, then determine efficacy
What is a druggable genome?
It is the number of genes that code for proteins that are druggable
What is the basic principles of drug target networks?
- One drug may target multipe proteins
- One protein may be binded by multiple drugs
What is the definition of druggability?
Ability fo a protein to be modulated by a drug-like small molecule, biologics, etc.
Drug should have complementary structure to the target site
What are the methods of assessing druggability?
- Sequence-based
- Predicted druggable based on sequence features (DNA, protein sequence) - Structure-based
- Protein structure contains drug-like pockets
- Protein binds to endogenous drug-like ligands - Ligand-based
- High affinity drug-like compunds available
- Compounds in clinical trials for the protein
- Protein is an established small molecule drug target
What is the current state of antibacterial drug development?
- Antibiotic discovery has slowed down
- reduced economic viability (small volume sold vs chronic drugs)
- increased liability claims for adverse events (they show up before company has had opportunity to make money from drug) - Antibiotic resistance is increasing (so new agents may also be ineffective)
What is the PASTEUR Act in the United States?
The governement has agreed to compensate pharma companies to develop new antibiotics.
This incentive is given because the value of new antibiotics to society is much greater
How are drug targets for antibacterial drugs chosen?
- Compare sequence of all strains and find what sections are conserved between all strains (they are probably essential for normal functioning)
- Ensure selected bacterial conserved sequence does not show up in the human genome (prevents the antibacterial from targeting the human)
- Mutagenic studies, knock out conserved proteins in bacteria and study impact
What are some commonly chosen targets for antibacterial drugs?
Targets should target organism without affecting the host. This is done by attacking processes that are critical to microbial well-being, but not mammallian systems
- Bacterial cell wall
- Inhibition of an enzyme unique to bacteria
- Disruption of bacterial protein synthesis
What is the benefit of using genomics to pharmaceutical development?
- Optimize pre-clinical therapeutic target
- Reduce R&D costs
- Maximize success of clinical trials
- Expedite FDA approvals
- Decrease time to market
What is the K-value paradox?
Complexity does not correlate with chromosome number
What is the C-value paradox?
Complexity does not correlate with genome size
What is the N-value paradox?
Complexity does not correlate with gene number
Why are mice the model of choice for pre-clinical drug discovery?
- Less ethically polarizing
- The human and mouse genome are similar and contain many of the same genes
What is the difference between pharmacogenetics and pharmacogenomics?
Pharmacogenetics: study of variability in drug response determined by a single gene
Pharmacogenomics: study of variability in drug response determined by multiple genes within the genome
What are the three categories of patients in terms of their response to therapy?
- Responders
- Non-responders
- Toxic responders
Why do some patients respond to therapy differently vs other patients?
- SNPs
- Ethnicity
- Age
- Disease
- DIs
See slide 53
What is the frequency of SNPs in an individuals genome?
SNPs occur with an average frequency of 1 per 300-1000
How frequent in the population does a single nucleotide mutation need to occur for it to be considered a SNP?
At least 1% of the population should have the SNP
What is a potential impact of a SNP that codes for a protein?
A SNP can potentially change the codon as read by RNA transcriptase
This eventually results in a protein with one amino acid that is different (can result in no effect, improved function, or reduced function due to changes in structure and function)
How does warfarin reduce blood clotting?
Inhibits the reduction of Vit K, and results in reduced clotting factor production
What are the three genes that are associated with Warfarin use?
- CYP2C9 gene (codes for an enzyme that breaks Warfarin)
- Variants of this gene need lower warfarin doses - CYP4F2 gene (codes for an enzyme that reduce ability to metabolize warfarin)
- Variants of this gene need higher warfarin doses - VKORC1 gene (codes for an enzyme that helps reduce Vitamin K)
- Variants of this gene need lower warfarin dose
What is the CFTR protein?
The CFTR protein functions as a chloride channel
What is the consequence of a CTFR protein mutation?
This mutation can result in the accumulation of chloride in lung membrane cells, causing water to enter and trigger the production of a thick, sticky mucous
This mucous can pose increased infection risk
What are the characteristics of Class I CFTR mutation?
NO CFTR protein (no chloride transport)
Therefore overproduction of mucous
What are the characteristics of Class II CFTR mutation?
Little to no CFTR protein (impaired chloride transport)
Overproduction of mucous
What are the characteristics of a Class III CFTR mutation?
Normal amount of CFTR protein, but no cloride transport (closed protein)
Overproduction of mucous
What causes the lack of CFTR protein in those who have a mutation on that gene?
In patients with CFTR mutations, they may have a SNP that causes a stop codon halfway through transcribing CFTR. This results in a smaller non-functional pre-CFTR protein
How does Ataluren improve symptoms associated with a CFTR mutation in Cystic Fibrosis?
Ataluren causes transcription to perform read-through transcription (skip the stop codon created by the mutation) and results in a fully formed CFTR protein
This treatment can result in creased number of CFTR proteins, increasing K+ transport out of the cell, and less mucous
What drug is used for therapy in Class III CFTR mutation Cystic Fibrosis?
Kalydeco can open up the endogenous CFTR protein and allow efflux of K+, which causes reduction in mucous production