531 Med Chem Unit 1 Lec1-4

Sources of Drugs

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