Studied by 15 people
Sources of Drugs
•Natural extracts
•Natural products
•Synthetic drugs
•New drugs from existing drugs
•Screening synthetic chemical libraries
•Screening Natural product libraries
•Rational drug design
•Serendipity (chance)
What is screening corporate chemical libraries
Screen old chemicals for activity/targets
Ex: Prontosil (red dye)
What is screening natural product collections
Ex: Screening plants from around the world→ Paclitaxel (anticancer drug)
What are natural products
pure molecules isolated from nature
-Tend to be larger and more polar
Synthetic Drugs example & carbon source?
-Carbon source is petroleum
Ex: Aspirin (acetylsalicyclic acid), chloral hydrate, chloroform, ether
New drugs from existing drugs examples
Ex: Antimalarial phenothiazine dyes, Chloropromazine (antipsychotic) to Imipramine (antidepressant)
Rational drug design Example
uses knowledge of drug target structure or enzyme mechanism to discover molecules that bind and modulate the activity of the target.
Ex: Pepsin & HIV
Serendipity drug example
Cisplatin (anticancer)
What are Important characteristics of a good drug
•Good oral bioavailability- water soluble but also small and lipophilic
•Chemically stable
•Chemically unreactive
•Metabolicallt stable- resistant to enzymatic breakdown in the body
•Pharmacologically specific- no off-target binding
•Potent but not too potent
•Good toxicity profile- wide therapeutic window
•Inexpensive to manufacture
Ionic Interactions
•Charge-Charge
•Often pH dependent
•Ions are solvated by water which competes with the interaction
Dipole & Dipole Induced Interactions
•Dipoles can be permanent or temp induced by a nearby charge
London Dispersion forces
•temporary attractive force that results when the electrons in two adjacent atoms occupy positions that make the atoms form temporary dipoles
•weakest intermolecular force
•bigger atoms have better LD
•Depends on polarizability
Hydrogen bonding
•N, O and H
•Special case of dipole dipole interaction
•strongest when linear
•Donor- the one that has the H attached
•Acceptor- has partial negative charge
•Proteins use Hbonding to interact w polar groups and intramilecular Hbonding to fold
Example of Hbonding importance to drugs
Ex: antibiotic vancomycin kills gram positive bacteria by clamping down on D-Ala-D-Ala terminus of its peptidoglycan thanks to a Hbond from the Vancomycin to the amine of the D-Ala-D-Ala
\n Ester formation means no H bond and weak binding
Cation Pi Interactions
•Non covalent interaction between the face of an electron rich pi system (ex benzene) and a nearby hard metal cation or an ammonium cation
•The more negative the ring surface is the stronger the cation pi interaction
Desolvation and the Hydrophobic Effect
• Placing nonpolar molecules in water is energetically unfavorable because the surrounding water molecules are more restricted in motion reducing the entropy of the system
•hydrophobic drug can bind and free the water
desolvation: The removal of solvent from material in solution.
Higher log P means__ polar
Less polar
Lower log P means ___ polar
More polar
high pi (hydrophobicity scale)
Higher pi means more more hydrophobic
Lower pi means more hydrolphillic
What is Log D
a pH dependent version of log P
At pH where the molecule is unionized logD=logP
How to estimate intrinsic binding energy
a summation of independent binding interactions
Cholinergic receptors
bind Acetylcholine
-Metabotropic
-Ionotropic
Metabotropic receptors
require G proteins and second messengers to indirectly modulate ionic activity in neurons
Ionotropic receptors
typically ligand-gated ion channels
Agonists
induce conformational change in their target receptor that triggers the signaling events
Mimics the full activity of the ligand
Antagonist
Blocks the effect of the liquid
Partial Agonist
Mimics the activity but plateaus at a lower level
Inverse Agonist
Has the opposite activity of the agonist
exerts opposite affect AND stops agonist affect
Effect
measure of biological output
→depends on binding but is a measurable action after binding takes place
Potency
measured along the x-axis by the ED50- the concentration of the ligand that gives 50% of its maximum effect
→ Less drug to get to 50% is more potent
Methadone is a __
a full agonist of the mu opioid receptor
Buprenorphine is a___
More potent but only a partial agonist si is less “efficacious”
Naloxone is a …
competitive antagonist and blocks the effects of both agonists and partial agonists
Competitive Inhibition
shift the activity curve of an agonist to the right. It takes more agonist to give the full effect
Noncompetitive inhibition
Affect both binding and activity & prevent agonist from achieving full effect by binding at a different site on protein
Affects maximum output
Affects efficacy but not potency
Therapeutic Index
TD50 / ED 50 (human)
LD50 / ED50 (animal)
TD50
Median dose of a drug at which 50% subject show toxicity (people or cells)
LD50
Dose at which 50% of animals die
ED50
Dose of drug which shows 50% efficiacy for a population of subjects
Safe drugs have high or low TI ratios?
HIGH because you want only a high dose to be toxic and a low dose to be effective
TI= TD50/ED50
Note
Flashcard