The drug discovery process Flashcards
True/False? It is easy and trivial to discover a drug
FALSE
What are the two strategies in drug discovery and how do they differ?
Target-Based discovery: you know what target (protein/enzyme) you want to hit
Phenotype-based discovery: You know the disease phenotype you want to treat
What is the difference between a first in class and a follower drug?
A first in class drug is a drug newly discovered through eg genomics or proteomics
A follower drug is one based off a follower drug with a slight modification
Which screening method has the highest rate of follower drugs? What does this imply?
Target-based approach
Suggests that once a MMOA has been established, target-based optimization does in fact work
What is the best method for lead discovery?
It depends
What is the difference between a hit and a lead?
A hit is just something that responded during a High Throughput Screening,
A lead is a hit that has been optimized and is of likely therapeutic value
Empirical data has shown that what types of molecules make good drug targets? Which don’t?
Enzymes, receptors and channels are good targets
Protein:protein interactions are not as good
Why can’t simple competitive inhibitors be readily developed despite many MMOAs being reported?
Because simple equilibrium binding of a drug at its active site is often times not sufficient for biological activity
What are two components that are required for efficient drug action?
Mass-action binding (concentration dependent)
Biochemical/structural rearrangements that shift the target away from mass-action binding, effectively locking the target in an inactive state
What are the 5 basic steps for structure-based drug design?
Target-selection
Structure determination of target
Pharmacophore identification or screening
Structure development of lead compound(s)
Lead candidate for biological assays and clinical trials
Define the biochemical approach of identifying targets
Basic research that leads to the elucidation of biochemical mechanisms of diseases
eg thalidomide’s target was discovered by fixing the drug to a column and running cell lysate over it to see what sticks
Describe the genetic approach of identifying targets
Mutations that predispose people to certain diseases
eg PARP + repair inhibitor leads to selective death in BRCA-deficient (breast cancer) cells
What is the point of target validation?
To prove that targeting a given protein will result in the desired biological outcome
What does target validation usually entail?
Establishment of biochemical mechanisms, hot spots (active sites), and CRISPR-KO/KIs to determine loss/gain of function
What are the two ways to identify hits?
High Throughput Screening
Structure-based approaches
Describe the HTS method of hit identification
“Brute force” method
A compound library is scanned for “primaries” based on properties, followed by more stringent “secondaries” to narrow down the list and eliminate false positives
Primaries are screened with a single high concentration of compound, whereas secondaries can be calculated over a range of concentrations, to identify hits that give rise to a IC50 curve
Define the structure-based approaches to identify hits
De novo/rational design: based on pharmacophore identification. Locate 3D position of key hydrogen bonds, electrostatic and hydrophobic interactions
Fragment-based discovery: Ligand that binds strongly is made of smaller, weakly-binding components that are joined together
Virtual screening: Computational research based on virtual screening of compounds deemed viable (Many false positives)
Define the pharmacophore of a drug
The part of the drug that actually causes a biological response
How can the pharmacophore be determined?
By inspection of a series of compounds with different activities towards the target
How is the pharmacophore defined?
By a number of features such as H-Bond donor/acceptors, hydrophobic groups, etc (defined in 3D with distances)
Define the Quantitative Structure-Activity Relationship model
A large number of similarly related drugs are split into two groups
One group is used to build a predictive model, and the other group is compared to the predictions of the first
Describe the process of lead optimization
Once a hit’s pharmacophore has been discovered, modifications are made to the molecule to effect its other properties (ADMET and DMPK)
What are the steps involved in lead optimization?
Start from one series of hits
Determine the molecular mechanism of action of hits through biochemical assays and structural studies
Increase potency by performind structure-activity studies (requires the generation of a series of analogs) - typically need to reach Kd in nanomolar range for efficacy
WHILE this is happening, optimize ADMET and DMPK
Why does the Kd of a lead need to be in the nanomolar range for efficacy?
Nanomolar Kd = residence time in seconds = stronger drug
Why do you optimize ADMET and DMPK at the same time as the Kd?
Because if you do it after you waste time and money
No sense in spending all this time on a drug with a great Kd only to figure out that eg it doesn’t cross BBB
How can you make a good rough compound for an enzyme?
By mimicking the natural substrate
How did they test anti-HIV protease drugs using isatin?
Isatin binds proline and forms a compound that absorbs yellow light very well
Treated HIV with isatin and inhibitor, if inhibitor did not work HIV protease would cleave protein leaving prolines which would bind isatin (yellow light still absorbed)
If inhibitor did work it would inhibit protease from binding isatin, yellow light would no longer be absorbed
What is a property of HIV (and many viruses) in terms of replication? What does this lead to? What does THAT lead to? How was this dealt with?
Very fast replication rate, very low fidelity (high error rate)
This leads to many daughter cells of HIV to have mutations, and those mutations can alter the active site, causing drugs to lose their efficacy
A drug (Darunavir) was developed to bind the amino acid backbone (which cannot mutate) to inhibit HIV protease activity
