Drug Development Flashcards
Outline the traditional route of drug development
A compound is found to have a physiological effect (eg a plant) and the molecular target is derived from this
Outline the modern route of drug development
A molecular target exists (eg enzyme) and a complementary compound is designed. The physiological effects are then analysed.
How does asparin provide a physiological affect?
Asparin acetylates a serine residue on cyclooxygenase, preventing the substrate from reaching the active site
What process is being blocked by asparin?
Prostaglandin synthesis
What features of chirality are important to consider when designing a drug candidate?
a. will one chirality be more effective
b. will the body alter the chirality of the drug candidate?
c. will one chirality have a detrimental affect
what is the difference between enantiomers and diastereoisomers?
enantiomers are non identical mirror images, all of which are chiral molecules (optically active)
diastereoisomers are not mirror images and are not necessarily chiral. Cis/Trans isomerisation
What factors determine L/D chirality?
The relative position of substituents to a reference compound (need a reference compound to be useful)
What factors determine +/- chirality?
The rotation of the plane of polarized light. (+ is clockwise)
What factors determine R/S chirality?
The absolute configuration around the chiral centre
What is the first rule when give R/S chiral compounds priority?
The atomic number of the attached compounds to the chiral carbon. The lowest atomic number is given the least priority
If the chiral carbon has one lone pair and one hydrogen bound (and two further groups) which will receive the lowest priority?
the lone pair
what is Ec50?
this is the concentration of ligand required to get a 50% biological response from your drug candidate
what is Ic50?
Ic50 is the concentration of inhibitor required to decrease target enzyme activity by 50%
Which part of ADME does Lipinskis rule of five apply to?
absorption
If a compound has a molecular weight of 700, partition coefficient of 2 and 7 H bond donor atoms, will it be well absorbed?
No, this molecule will have poor absorption according to lipinskis rule of 5
What is the partition coefficient?
ratio of how well a molecule dissolves in organic solvent vs water. (this is a direct correlation to how well a molecule will dissolve in a biological membrane)
If a compound is not soluble in the bloodstream, how will it be transported?
It will be association with HSA - human serum albumin
What structural feature of HSA makes it appropriate for its role in drug delivery?
It has an alpha helical structure which has pockets to hold hydrophobic residues
What are the two steps of metabolism of xenobiotic compounds?
- oxidation 2. conjugation
What is the purpose of oxidation of foreign molecules?
Oxidation marks the compound as xenobiotic.
What enzyme catalyses the oxidation of iboprufen?
Cytochrome p450 catalyses the hydroxylation reaction in the liver
What else is require for the oxidation of iboprufen in the body, other than the enzyme?
NADPH and 02
Despite metabolism being the bodily process used to discard of the xenobiotic compound, what affect might the conjugation of a foreign body have?
Conjugation can often make the conjugate molecule more active than the drug before conjugation as they are hydrophilic, making the drug more soluble.
Briefly describe Erythrocytic Cycling
Molecules which are too large to be filtered through the kidneys will be actively transported in bile to the intestine. Further metabolism will then occur either turning the compound into stool or it can be reabsorbed into circulation via the liver
Which compounds will and will not be filtered out by the kidneys in excretion?
Molecules smaller than 60KDa will be filtered out by the kidneys, molecules associated with HSA will not be filtered out (HSA - 65KDa)
How can drug toxicity limit the effectiveness of a drug?
The drug could modulate the target too effectively, the drug might have off target effects, the drug might have toxic metabolic by-products.
