Requirements Of An Effective Drug Flashcards
What are the top selling drug structures?
Lipitor, Crestor, Seroquel, Nexium, Plavix, Seretide, Abilify
Many have complex structures- not easy to make
All contain many hetero atoms (N,O,S) - hydrogen bonding
Some contain halogens F and Cl
What are the requirements of an effective drug?
Stable enough to reach target in sufficient quantities
Able to reach target biochemistry
Interact specifically with target to produce correct espouse
Not interfere severely with non target biochemistry
Not metabolised too quickly
Metabolised to non-toxic degradation products
What is lipski’s rule of 5?
Guidelines detailing, drug with ideal absorption or permeation should be
MW < 500 Da
LogP < 5
Hydrogen bond donors < 5 (this = sum of all atoms connected to H)
Hydrogen bond acceptors < 10 (this is the sum of Os, Ns and Ss)
What compounds are exceptions to lipski’s rule of 5?
Compounds that are substrates for biological transporters
What are examples of drugs which fail the lipski’s rule of 5?
Methotextrate, common anticancer drug.
This has 8 h bond donors + 13 h bond acceptors
Erythromycin has MW 719 and 14H bond acceptors.
How are erythromycin and methotextrate successful drugs if they fail the lipski’s rule of 5?
Both of these drugs are absorbed on to carrier proteins when taken orally and transported throughout the body to the site of action
How does sulfanilamide work?
Inhibits enzyme dihydropteroate synthase involved in formation of folic acid.
Folic acid is a final precursor for DNA synthesis.
We can halt the microorganism synthesis of folic acid as a selective way of killing bacteria in humans
How does sulfanilamide bind?
Through maximising favourable electrostatic interactions.
Electron rich areas in inhibitor bind near electron poor regions in enzyme and vice versa
What is the state of the H in a Hydrogen bond?
The H is electron poor and the heteroatom is electron rich
What is one method of modulating drug metabolism?
Add halogen atoms like Cl and F to drugs,
These atoms are into to common in normal biological molecules, and body often has difficulty metabolising these.
F is often used at the position where enzymes in body cause metabolic changes to drug. Presence of F slows metabolism which increases plasma duration of drug
What is Prevacid?
Proton pump inhibitor, used to treat stomach ulcers.
Originally was made un-fluroated, but found only to have a half life of 54 minutes,
Replacing methyl group with trifluromethyl group increased the half life to 780 minutes, which is a more suitable time frame for a pharmaceutical product
Why are F preferred over Cl to increase plasma duration?
F is small like a H, allowing it to still fit into the binding pocket of the receptor
Cl is much larger, so exchange with a H is often not possible. Cl is also very electronegative, often placed with molecules to increase electrostatic interactions between the drug and its target
What is the result of producing the tricholoromethyl analogue of Prevacid?
Much longer half life, 50 hours, but found only to have 1/100th biological activity due to increased size of tricholoromethyl group inhibited drug interacting with desired biological target as Cl was too big
What does alkaloid mean?
Containing a basic nitrogen
Why is interaction specifically with the target to produce the correct response such an important requirement of a drug?
One of the fundamental precept or med chem is that small molecule drugs interact with their biological targets in a specific manner which is similar to a lock and key concept.
Many human diseases result from an imbalance in enzyme or receptor function
Therefore, small molecules which interact specifically with the target can modify the tarts function, halting the disease
