Thatcher - Drug Discovery

Question 1

Amoxicillin

Answer 1

• 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

Question 2

Amoxicillin

MOA

Answer 2

• PBP + Serene Protease + Base
  
  • Blocks peptide from linking
    
    • –> Stops cross linking of bacterial cell wall
• Acyl Enzyme Intermediate
  
  • ​= tetrahydral intermediate
    
    • –> 1 peptide to another peptide

Question 3

Benzodiazapines

Alprazolam / lorazapam / diazapam

Answer 3

Potentiate Actions of GABA

–> Increase Receptor Affinity

• GABA = INHIBITORY NT
  
  • Increasing the affinity –> Sedation
    
    • ​Anxiolytic Activity
• DESENSITATION of the GABAa receptor
  
  • ​–> Downregulation (chronic therapy)
    
    • ​–> ADDICTION / TOLERANCE

Question 4

Glutamate Receptors

Answer 4

Green Light

Excitatory Receptor

Glutamic acid –> excitatory NT –> Glutamatergic receptors

Question 5

GABA / Glutamte Receptors

Answer 5

• 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

Question 6

Status Epilepticus

Epilepsy

Answer 6

• 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

Question 7

Agonist

of GABA

Answer 7

Benzodiazapines

• INCREASE inhibitory transmitter GABA potency
  
  • –> Prevent convulsions
  • Prevent epilepsy
  • Reduce Excitory fxn

Question 8

Inverse Agonist

of GABA

Answer 8

• DECREASE GABA potency
  
  • ​expected to give opposite response of agonist
    
    • instead it just decreases the potency
  • ​PROCONVULSIVE
    
    • ​causes convulsios

Question 9

Antagonist of GABA

Answer 9

Bind to GABA but DO NOT HAVE AN EFFECT

FLUMAZENIL

used to BLOCK OVERDOSE FOR BZDS

Question 10

Issue With BZD’s

Answer 10

Entirely SYMPTOMATIC

we are treating symptoms not the disease or underlying cause

• Prescribed for:
  
  • Anxiety / Panic Attacks / Depression
  • Withdrawal / Insomnia / Sedation

Question 11

Pharmacophore of

BZD

Answer 11

• Key Bindings
  
  • Hydrophobic Binding
  • Covalent Bonds
  • VDW Interactions

Question 12

Cannabimimetic Prodrug

Answer 12

• Acetaminophen MOA is not very well understood
  
  • One possible MOA is:
    
    • APAP –> Fatty Acid AMino Hydrolase
      
      • = CannabiMIMETIC inhibitor of ANANDAMIDE Reuptake
      • TRPV1 Agonist / analgesic
• Anandamide = receptor agonist for CB1
  
  • blocking its re-uptake –> analgesic effects

Question 13

Orphan Drug Act

Answer 13

• FDA offering FASTRACKING for a drug
  
  • that targets Neglected diseases
    *

Question 14

Drug Discovery Landscape

Answer 14

• 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

Question 15

Human Genome Project

Answer 15

• 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

Question 16

-OMICS

Genomics / transcriptomics / proteomics / metabomics

epigenomics

Answer 16

• Catch word that attracts attention
• ​LEADS TO –> Big Data that we can analyze
  
  • –> Produce a PREDICTIVE network
    
    • –> PERSONALIZED MEDICINE

Question 17

Phenotypic Screen

Drug Discovery

Answer 17

• 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

Question 18

Target Based Screen

Drug Discovery

Answer 18

• 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
• Disadvantages
  
  • Biased towards potentially flawed/incomplete understanding of pathology
  • Inability to predict biological compensation
  • Can be a bad target / not useful

Question 19

Drug Discovery Cycle

Optimization

Answer 19

• Hits + Leads
• ITERATIVE OPTIMIZATION
  
  • ​can improve through repitition
• SAR
  
  • structure activity relationships

Question 20

PAINS

Pan Assay Interface Compounds

Answer 20

• Frequent Hitters
• Compounds that have MULTIPLE activities in the body
  
  • like priveledged structures
  • HARD TO OPTIMIZE
• Quinones / Catecholes
• Curcumin
• Enones / Phenol / ENE / Toxoflavin

Question 21

Molecular Rules & Filters

Ex. Veber / Lipinski / Murphy

Answer 21

• Shortcuts for drug discovery
• Statistically helped determine if a drug is more
  
  • ​BIOAVAILABLE

​DOES NOT IMPLY EFFICACY

Question 22

Lipinski’s Rule of 5

Answer 22

Rule for Oral Bioavailability

does not imply efficacy

• LogP
• HBD
• HBA
• determined from >200 drugs in clinical or clinic trials

Question 23

Designer Drugs

Answer 23

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