Thatcher - Drug Discovery Flashcards
(23 cards)
Amoxicillin
- Penicillin Antibiotic - PBP Peptidase Enzyme Inhibitor
- mimics D-ALA-D-ALA scissile bond
- Covalent Acyle enzyme intermediate
-
Beta Lactam Ring
- –> Cross linking –> Blocks Bacterial Wall Synthesis
Amoxicillin
MOA
-
PBP + Serene Protease + Base
- Blocks peptide from linking
- –> Stops cross linking of bacterial cell wall
- Blocks peptide from linking
-
Acyl Enzyme Intermediate
-
= tetrahydral intermediate
- –> 1 peptide to another peptide
-
= tetrahydral intermediate
Benzodiazapines
Alprazolam / lorazapam / diazapam
Potentiate Actions of GABA
–> Increase Receptor Affinity
-
GABA = INHIBITORY NT
- Increasing the affinity –> Sedation
- Anxiolytic Activity
- Increasing the affinity –> Sedation
-
DESENSITATION of the GABAa receptor
-
–> Downregulation (chronic therapy)
- –> ADDICTION / TOLERANCE
-
–> Downregulation (chronic therapy)
Glutamate Receptors
Green Light
Excitatory Receptor
Glutamic acid –> excitatory NT –> Glutamatergic receptors
GABA / Glutamte Receptors
- There are MANY of these ionotropic receptors
- very rapid, many are GPCR’s
- Complex system but..
-
Hitting just 1 of the transporters
- –> Very effective drug
-
Hitting just 1 of the transporters
Status Epilepticus
Epilepsy
-
First line Treatment = Benzodiazepines (BZD)
- They prevent epilepsy & reduce excitory function
-
Agonist of the Gaba Receptor
- increase the inhibitory transmition of GABA
-
Gamma(y2)2 subunit dysfunction of GABA
- associated w/ childhood absence epilepsy
Agonist
of GABA
Benzodiazapines
- INCREASE inhibitory transmitter GABA potency
- –> Prevent convulsions
- Prevent epilepsy
- Reduce Excitory fxn
Inverse Agonist
of GABA
-
DECREASE GABA potency
-
expected to give opposite response of agonist
- instead it just decreases the potency
-
PROCONVULSIVE
- causes convulsios
-
expected to give opposite response of agonist
Antagonist of GABA
Bind to GABA but DO NOT HAVE AN EFFECT
FLUMAZENIL
used to BLOCK OVERDOSE FOR BZDS
Issue With BZD’s
Entirely SYMPTOMATIC
we are treating symptoms not the disease or underlying cause
- Prescribed for:
- Anxiety / Panic Attacks / Depression
- Withdrawal / Insomnia / Sedation
Pharmacophore of
BZD
-
Key Bindings
- Hydrophobic Binding
- Covalent Bonds
- VDW Interactions
Cannabimimetic Prodrug
-
Acetaminophen MOA is not very well understood
- One possible MOA is:
- APAP –> Fatty Acid AMino Hydrolase
- = CannabiMIMETIC inhibitor of ANANDAMIDE Reuptake
- TRPV1 Agonist / analgesic
- APAP –> Fatty Acid AMino Hydrolase
- One possible MOA is:
- Anandamide = receptor agonist for CB1
- blocking its re-uptake –> analgesic effects
Orphan Drug Act
-
FDA offering FASTRACKING for a drug
- that targets Neglected diseases
*
- that targets Neglected diseases
Drug Discovery Landscape
-
Less and Less drugs are being made
- R&D funding is slashed and researchers are being laid off
-
Pharma is focused on blockbusters
- not on orphan drugs or neglected diseases
-
ROI = Return on Investment IS FALLING
- DNA sequencing isnt producing many drugs
Human Genome Project
-
Only a small & of genes are related to pathogens/disease
- So not many drugs are being made from this advancement
- Only Genetic Diseases are helped due to this advancement
-OMICS
Genomics / transcriptomics / proteomics / metabomics
epigenomics
- Catch word that attracts attention
-
LEADS TO –> Big Data that we can analyze
- –> Produce a PREDICTIVE network
- –> PERSONALIZED MEDICINE
- –> Produce a PREDICTIVE network
Phenotypic Screen
Drug Discovery
- Cell Based HTS –> Hits/Leads –> Target deconvolution
- Advantages:
- in vivo / druggable argets
- Avoid biilogical complexity
- Unbiased with mechanism
- Disadvantages:
- Dependent on disease model relevance
- Requires robust/scalable phenotypes
- Complications in metabolism & pereability
- SAR
Target Based Screen
Drug Discovery
-
Target Validation -> IN VITRO HTS –> hits/leads
- HTS = high throughput screening
-
Advantages:
-
Defined Target / mechanism of action
- with biochemical assays
- Easier path to structure based drug design + SAR
- = structure activity relationship
-
Defined Target / mechanism of action
-
Disadvantages
- Biased towards potentially flawed/incomplete understanding of pathology
- Inability to predict biological compensation
- Can be a bad target / not useful
Drug Discovery Cycle
Optimization
- Hits + Leads
-
ITERATIVE OPTIMIZATION
- can improve through repitition
-
SAR
- structure activity relationships
PAINS
Pan Assay Interface Compounds
- Frequent Hitters
- Compounds that have MULTIPLE activities in the body
- like priveledged structures
- HARD TO OPTIMIZE
- Quinones / Catecholes
- Curcumin
- Enones / Phenol / ENE / Toxoflavin
Molecular Rules & Filters
Ex. Veber / Lipinski / Murphy
- Shortcuts for drug discovery
-
Statistically helped determine if a drug is more
- BIOAVAILABLE
DOES NOT IMPLY EFFICACY
Lipinski’s Rule of 5
Rule for Oral Bioavailability
does not imply efficacy
- LogP
- HBD
- HBA
- determined from >200 drugs in clinical or clinic trials
Designer Drugs
Simple Synthetics can be More Potent
than complex natural products
or endogenous messenger models
- Ex. Morphine / Met-enkephalin
- NON FDA APPROVED
- mimic the natural enkephalins
