L8 + L9 Rational Drug Design DT

Question 1

What is Molecular Pruining? example?

Answer 1

Molecular Pruning is a method of drug design that involves chipping away portions of a biologically active molecule to evaluate the pharmacopohre. The non-interactive part may interact with the receptor via steric interactions. An example is morphine. Its pharmacophore is identical to that of methadone

Question 2

Explain how conformationally restricted drugs is an example of Rational Drug design (RDD).

Example?

Answer 2

Conformationally restricted drugs are hindered from rotation, and this enhances the interaction abilities of the drug, making it more potent. Etorphine is more potent than buprenorphine due to the additional presence of a double bond in its stucrure

Question 3

Explain how Bioisosteres are an example of RDD

Answer 3

Bioisosteres work by replacing the the group or substituent of a drug with another similar group that enhances the drugs characteristics. This can improve metabolism, selectivity, decrease toxicity and improve pharmacokinetic profiles. Tolbutamides bioisostere is chlorobutamide which avoids metabolism and is longer lasting

Question 4

Explain how conjugates are an example of RDD

give examples

Answer 4

Conjugates involve joining two different entities to gain a synergystic therapeutic effect. e.g

• Drug-Drug (involves two drugs linked together such as aspirin-paracetamol)
• Antibody-Drug (antibiody enables the drug to target tumor cells based on the receptors on the surface e.g Brentuximab

Question 5

How is a prodrug an example of RDD

give examples

Answer 5

A prodrug is a drug that is converted to the biological active state via hydrolysis or enzyme reactions.
Type 1 prodrug is converted into the biological active form within the cell e.g statins
Type 2 prodrug is converted -> active form outside of the cell e.g salicin

Question 6

How are biochemical and Physiological studies examples of RDD give examples

Answer 6

They have led to the discovery of ranitidine which was developed through biological studies of histamine.

Another example is L-Dopa which was discovered through biological studies of dopamine

Question 7

How has structural biology methods led to RDD?

give examples

Answer 7

It has been used to determine the gross stucture of a protein or a receptor and then screen physcially or virtually.. Gleevec is an example of a drug discovered this way. it is a Tyrosine-Kinase inhibitor in CML

Question 8

How is Genetics an example of RDD?

give examples

Answer 8

Genetics can be used to identify a gene to switch off its prolematic function or upregulate a gene if its expression is deficient. Genes can also be replaced. Pyrrole is an example of a drug that inhibits enzymes involved in Enzyme processing such as heliciases and RNA polymerase

Question 9

Discuss how we can target RNA

Answer 9

For targeting RNA, you can use the antisense approach by using drugs like Formivision. Issues that arise involve:

• RNA being prone to enzymatic cleavage. Use nanoparticles which can envelope the SiRNA to avoid degredation in the blood stream
• Drug delivery can result in unwanted immune responses (hence use nanoparticles for better selective targeting)

Question 10

discuss RNA agent modifications

Answer 10

3 types:

Chemically modified SiRNA - by altering the sugarphosphate backbone on the RNA improves its stability
Expressed RNAi - involves using a vector so that the SiRNA can be expressed internally rather than being delivered externally
Micro RNA - a small non-coding RNA molecule found naturally in plants and animals that regulates gene expression through transcription and post transcription

Question 11

list all methods of Rational Drug Design

Answer 11

Molecular pruning
Bioisosteres
Drug Conjugates
Prodrugs
Structural biology approaches
Biochemical and Phyisological approaches
Genetics
RNA