introduction Flashcards
most drugs are molecules but
most molecules are not drugs
it is the applied science that is focused on the design (or discovery) of new chemical entities (NCEs) & their optimization & development as useful drug molecules for the treatment of disease processes
medicinal chemistry
isolated morphine from opium
Serturner
emetine from ipacacuanha
Pelletier
digitalis from dropsy by
william withering
isolation of cocaine & physostigmine from calabar bean by
Nieman
-receptor concept
-chemotherapeutic agents possesses haptophoric & toxophilic groups
*chemotherapeutic agents + receptor = chemical reactions
*labile, versatile, but not firmly bound
-methylene blue, salvarsan, trypan red
-drug resistance
Paul Ehrlich
-ancient folk medicine + natural product chemistry
-directed to new & natural or synthetic organic compounds
-devoted to the discovery & development of new agents for treating diseases
-concerned mainly with organic, analytical, & biochemical aspects of drug discovery
-explores the relationship b/w chemical structure & observed biological activity
-principal domain
*application towards drug design
-highly interdisciplinary
-hallmark of med chem research
*understanding SARs at the level of physical organic properties w/ consideration of molecular confirmation
medicinal chemistry
uses physical organic principles to understand the interaction of small molecular displays with the biological realm
working definition
medicinal chemistry
Paul Erhardt (2002)
merges both the basic & applied nature of med chem’s scientific activities into a key mix of endeavors for w/c a new research paradigm exists
med chem
2 phases of drug design
1- basic concepts of drugs, receptors, & drug-receptor interaction
2- clinical application of concept of drug interactions
basic concepts of drugs, receptors, & drug-receptor interaction
3 steps
1- properties that turn a molecule into a drug
2- properties that turn a macromolecule into a drug target
3- designing & synthesizing a drug to fit into the target
clinical application of concept of drug interactions
3 approaches
1- manipulation of the body’s endogenous control systems
2- manipulation of body’s endogenous macromolecules
3- inactivation of harmful exogenous substances
stages of drug discovery, design & development
1- drug discovery
2- drug design
3- drug development
stage 1
Target ID & Validation
choosing a disease
-diseases where there is a need for new drugs
-prevalent disease
-economic factors
-orphan drug
stage 1
Target ID & Validation
*choosing a drug target
-target specificity & selectivity
-multitarget
*the chosen target may over time lose its sensitivity to the drug
stage 1
Target ID & Validation
identify a bioassay
determines activity of the compound at the target & other receptors
-in vitro: in an artificial environment (test tube, culture media)
-in vivo: in the living body
-ex vivo: doing the test on a tissue taken from a living organism
Ames test
-in vitro
-salmonella typhimurium
hERG test
both in vivo & in vitro
acute toxicity tests on mice
in vivo
lead discovery
-finding a lead compound
*screening of natural products
-plant, microorganisms, marine sources, animal sources, venoms & toxins
*existing drugs
-SOSA- selective optimization of side activities
-natural ligands/ substance/ modulator
*combinatorial synthesis
lead discovery
chromatography
isolation and purification
lead discovery
X-ray crystallography
NMR spectroscopy
structure determination
-involves the automated testing of large numbers of compounds vs a large number of targets
-several thousand compounds can be tested at once in 30-50 biochemical tests
-effects measured: cell growth, color change for an enzyme catalyzed reaction, or displacement of radioactive labelled ligands from receptors
high throughput screening
- test of drug receptor binding
*NMR spectrum of drug is taken, the protein is then added & the spectrum is re-run
*if the drug fails to bind to the protein, then the NMR spectrum will still be detected
*if the drug binds to the protein, it becomes part of the protein, nuclei will have a shorter relaxation time & no NMR spectrum will be detected
NMR spectroscopy
nuclear magnetic resonance spectroscopy
NMR spectroscopy
-pharmaceutical companies have prepared thousands of compounds
-they are stored in the freezer, catalogued & screened on new targets as these new targets are identified
synthetic banks
if one know the precise molecular structure of the target (enzyme or receptor), then one can use a computer to design a perfectly fitting ligand
*most commercially available programs do not allow conformational movement in the target (as the ligand is being designed / docked into the active cells)
*most programs are somewhat inaccurate representations of reality
computer assisted drug design
a chance of occurrence
-must be accompanied by an experimentalist who understands the big picture (¬ solely focused on immediate research goal), who has an open mind toward unexpected results, & who has the ability to use deductive logic in the explanation of such results
example: -antabuse discovery
-development of sildenafil to treat ED during research for heart drug
serendipity
yew tree
taxus brevifolia
paclitaxel
Qinghao
artemisia annua L.
artemisinin
poppy
papaver somniferum L
morphine
penicillium notatum
penicillin
horse shoe crab
limulus polyphemus
Limulus Amebocyte Lysate (LAL)
epipedobates tricolor
epibatidine
marine cone snail
conus geographus
ziconotide
gila monster
heloderma suspectum
exenatide
brazilian viper
bothrops jararaca
teprotide
sulfonamide is converted into
tolbutamide & chlorothiazide
warfarin to
tipranavir
lead optimization
goals of drug design
1-doog selectivity & level of activity for its target
2-improve pharmacokinetic properties
3-improve interaction w/ target
4-easily synthesized
5-chemically stable
6-minimal side effects
7-non-toxic
structure activity relationships (SARs)
-part/group of the ,olecule important to biological activity
-identification of pharmacophore
*important binding groups w/c are required for activity
drug optimization goals
-optimizing hydrophobic/ hydrophilic properties
-resistance to chemical & enzymatic degradation
-resistance to drug metabolism
-optimize targeting of drugs
-reduce toxicity
-development of prodrugs
-drug alliances
-endogenous compounds
-peptides & peptidomimetics
drug optimization strategies
-variation of substituents
-extension of the structure
-chain extension/ contraction
-ring expansion/ contraction
-ring variations
-ring fusions
-simplification of the structure
-rigidification
-conformational blockers
isosteres
atoms or group of atoms w/c have the same valency (# of outer shell electrons) & w/c have chemical or physical similarities
bioisoteres
biologically-active compounds containing an isostere
toxicity testing
-acute
-subacute
-chronic
-reproductive toxicity & teratogenicity
-carcinogenicity
-mutagenicity
-investigative toxicology
clinical development
phase 1
20-100 volunteers
clinical development
phase 2
100-500 volunteers
clinical development
phase 3
1,000-5,000 volunteers
phase 4
post approval
out of every 10,000-15,000 new compounds identified during discovery
-5 are considered safe for human testing
-1 of these compounds is typically approved as a marketed drug
