LECTURE 5: THE DRUG DISCOVERY PROCESS Flashcards
Drug Discovery Process: OVERVIEW
1) what are the portions of discovery
2) what comes after discovery (2 processes)
1) Discovery
o Target ID
o Hit ID
♣ Lead with biological activity
o H2L
o Lead optimization
2)
- Pre-Clinical
- Clinical Trials
Drug Discovery Process: OVERVIEW
1) what composes target-based discovery (as steps)
2) what composes phenotype-based discovery (as steps)
1)
o Identify the key target in disease
o Identify hits
o Lead optimization
o Clinical trials
2)
o Identify the disease phenotype
♣ Trying to change phenotype associated with disease
o Identify hits
o Lead optimization
o Clinical trials
Which Strategy (target based or phenotype based) Works Best?
1) what offered hope that target based drug design would lead to more cures
2) was there a poor return on investment in target based drug discovery? why
3) what technique produces more NME
4) for discovery of follower or me too drugs, what technique is higher
5) what does this suggest
1) Rise of genomics, proteomics + structural biology
2) yes, fewer first in class NME discovered through target based approaches
- Because of the fact that there is a poor/incomplete understanding of the complexity of disease
3) Phenotypic screening produces more first-in-class drugs
4) The rate of innovation for “follower” or “me too” drugs is higher for target based approaches
5) This suggests that once a molecule mechanism of action (MMOA) has been established –> optimization through target based approaches is efficient
Discovery vs Optimization:
1) after identifying phenotype what happens
2) what are phenotype based approach based on
3) so, what strategy is for the discovery to them be optimized best?
1) screen compounds that effect phenotype
2) based approach are based on cellular or physiological assays
3) Phenotypic discovery will ‘win’
o In other diseases, structure based discovery ‘wins’
Process of Structure-Based Drug Design:
1) name all steps
1) target selection
2) structure determination of target
3) pharmacophore identification or screening to identify lead compound
4) development of lead compounds
5) lead candidate for biological assays + clinical trials
6) 3+5+5 lead to structure determination of target with compounds
Process of Structure-Based Drug Design:
1) Target selection
a) what does it depend on
b) because its dependent on this, what does it ensure (why is this important)
1)a) depends on what the disease is
b) ensures selectivity, makes sure the drug doesn’t target human protein (or another target)
Process of Structure-Based Drug Design:
2) Structure determination of target
a) where can we find the structure
2)a) PDB
Pharmacophore identification or screening to identify lead compound
3) what is the pharmacophore
3) the part that really matters –> core of the drug you want to build upon
Development of lead compounds:
4) what does this comprise of
4) optimization
Lead candidate for biological assays + clinical trials
5) what does this entail and in what process of drug discovery
5) Further optimization for ADME
i. These things are all unrelated to affinity
ii. Whether lead is sufficient for clinical trials
Hit Identification: SCREENING
1) What is a hit
2) what are the 2 methods to identify hits
1) a compound that has the desired biological or chemical properties in an assay
2) HTP and structure-based approach
Hit Identification:
1) within structure based approach, what are the different methods
1) denovo + fragment-based discovery + virtual screening
Hit Identification: SCREENING
1) What does the process of HTP require
2) what does is the first screen performed for/with
3) what does the 1st screen look like
4) what are potential measurement outputs of 2nd screening
1) Requires robust assay to test activity or potency of each compound in library
2)
1st screen:
- First performed to identify hits
- Performed with a single high concentration of compound
2nd screen:
- Performed with range of concentration
♣ In order to identify hits that give rise to IC50 curve
3)
1st screen:
- Followed by more stringent secondary screens to narrow down the list of hits + eliminate false positives
2nd screen:
♣ Colorimetric
♣ FP
♣ High-content imaging of cells automated microscopy
Within structure based approach
1) what are we trying to mimic in drugs
1) substrate mimicry or transition state analog (for comp inhibitors)
Within structure based approach - DeNovo (or rational design)
1) based on what
2) what is located in 3D in the structure based approach
3) what are the drugs typically (type of drug)
1) pharmacophore identification
2) Locate the 3D position of the key H-BONDS, electrostatic and hydrophobic interactions
3) Typically, structural analogs of natural ligands or existing drug
