5- discovery leads part II

Question 1

what is combinatorial chemistry? what is tested based on academic and industry? and, what is based on?

Answer 1

another way of discovering leads – make mixtures of molecules and test mixture, using specialized methods based on activity of mixture- which molecules are behaving in the way you’re interested in. testing mixtures is based on academics and testing impure single products is based on industry. it is based on the idea of darwinian selection

Question 2

what is the problem with combinatorial chemistry?

Answer 2

although you can make big molecules mixtures quickly, getting information out is more difficult

Question 3

explain the general steps of doing a combinatorial search. explain core, appendage, and deconvolution (4 points)

Answer 3

• make a large mixture (library) of molecules
• structures have common “core” (the part of the molecule that remains consistent) and random “appendages” (the different substituents attached to the core)
• test the compounds as a mixture
• ”deconvolute”(remove the compounds one at a time in order to analyze them) the result from the mixture to identify molecules that show desired properties

Question 4

what drug has been discovered by doing a combinatorial search?

Answer 4

sorafenib (specialized anti cancer molecules)

Question 5

what is de novo design? what does it require? and how is it obtained?

Answer 5

final method to discover leads. requires 3-D structure of biological target. obtained from: X-ray crystal structure.

Question 6

what do de novo designs start out with? what is designed?

Answer 6

start with a protein structure and build a computer model of it. design a molecule that fits this pocket (prevents other chemical reaction, and can treat the disease).

Question 7

what is lead optimization? who and what is involved?

Answer 7

process by which a drug candidate is designed after an initial lead compound is identified. mostly chemists, are involved but some biochemists to do testing and verification of materials

Question 8

explain the 6 steps in lead optimization

Answer 8

• make small changes in a drug structure and look for changes in activity
• identify parts of drug molecule that interact with biological target
• try to optimize as many properties as possible (solubility, acidity, basicity)
• use overall properties to predict what will happen to drug when it goes inside body → optimize as many properties as possible
• try to target the properties that are known to give good activity in drug materials

Question 9

what is SAR and SPR and what is the difference?

Answer 9

• SAR is structure activity relationships and SPR is structure property relationships. the difference is that SPR in principle work the same way but the difference is that the number of tests is larger, and decision making process is based on larger number of variables

Question 10

explain the steps of SAR as a process

Answer 10

haha……….

Question 11

what two properties does SPR optimize simultaneously? explain both

Answer 11

• potency (refers to dose that produces bio activity- when you say something is potent, the dose becomes smaller- you want the lowest dose possible)
• selectivity (ratio between dose that gives desired biological activity vs dose that gives undesired biological activity → want largest dose for undesired biological activity )

Question 12

what are the 7 other properties that SPR optimize?

Answer 12

• solubility (water)- has to dissolve in our bodies
• lipophilicity (solubility in non-polar solvents)- our membranes made out of materials that have properties like gasoline
• chemical stability (time and conditions for decomposition)
• acid-base behavior
• susceptibility to metabolism (how fast and what type)
• toxicity (nature and dose) (change isn’t poisonous)
• ease of synthesis (fast)

Question 13

explain the steps of SPR as a process (diagram)

Answer 13

heeeheeeheeee

Question 14

what is the hardest problem in medicinal chemistry? explain a bit

Answer 14

hardest problem is getting drugs into the body. you want “drug like” molecules- easy to get in and out of the body. certain properties correlate well with drug performance → optimize these all at the same time as potency is optimized

Question 15

what is the end result of the discovery phase? how long does the process take?

Answer 15

chemical properties + basic biological profile is known. this takes 1 to 3 years

Question 16

why do companies identify 3 or 4 backup compounds?

Answer 16

if primary compound fails, you minimize recovery time. the backup compounds need a bit of structural variety.