Lec 7 LOs

Question 1

Explain the concept of QSARs.

Answer 1

Quantitative structure-activity relationship
They are mathematical models describing the correlation between drug structures and activities
- Derived from statistical regression
Information of the receptor is not necessary

Question 2

List the structural descriptors used for simple QSAR models.

Answer 2

Molecular descriptors
Numerical parameters describing chemical properties that can be directly determined by the drug structure
- Used as variables in QSAR variables
Examples
– Drug as a whole: LogP, LogD, molecular weight, pKa
–Fragments: pi values, sigma values, size

Question 3

Distinguish the use of the training set and the test set in QSAR modeling

Answer 3

Training is phase 1
– Determines parameters (P1,P2, etc.) of a mathematical model using a training set
Testing is phase 2
– Checks the validity of the model using a test set
–> Both training set and test set contain drugs with known activity data
–> Only validated, model can be used to predict the activity of the drugs without known activity data

Question 4

Explain different approaches for lead discovery and lead optimization.

Answer 4

• Drug discovery and development process
• Basic research
• Target
• Lead
  – Discovery
  »»Natural products
  »»Antimetabolites
  »»Structure-based drug design
  »»High throughput screen
  »»In silico drug design
  – Optimization
  »»Structure-based drug design
  »»QSAR
  »»Isosteric replacement
  »»prodrug
• Drug candidate
• Preclinical and clinical trials

Question 5

Explain the uses of bioisosteres.

Answer 5

Functional groups or atoms that have a similar steric and electronic properties and produce similar effects on targets
Uses
–Improve pharmacokinetics
–Improve selectivity
–Simplify the synthesis process
–Reduce side effects
–Avoid patent issues

Question 6

Explain the uses of prodrugs.

Answer 6

Inactive or carrier form of a drug that is transformed in vivo to the active drug form
- Uses
– Prolong or shorten the duration of action
– Help localize a drug to a specific target site
– Take advantage of active transport processes
– Solve a formulation problem
– Decrease toxicity or side effects

Question 6

Explain how prodrugs are activated via in vivo.

Answer 6

Enzymatically
- Example: remdesivir
—It is a prodrug
—Enzymatically converted to a nucleotide analog, where interferes with viral RNA production

Question 7

How can you propose a structural change to increase affinity when the structure of a drug in the binding pocket is given?

Answer 7

Structure based design
We want a snug binding pocket so a water molecule cannot get in
Once we add something and hydrogen bond there is not a gap and then there is better and much tighter binding