introduction

Question 1

most drugs are molecules but

Answer 1

most molecules are not drugs

Question 2

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

Answer 2

medicinal chemistry

Question 3

isolated morphine from opium

Answer 3

Serturner

Question 4

emetine from ipacacuanha

Answer 4

Pelletier

Question 5

digitalis from dropsy by

Answer 5

william withering

Question 6

isolation of cocaine & physostigmine from calabar bean by

Answer 6

Nieman

Question 7

-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

Answer 7

Paul Ehrlich

Question 8

-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

Answer 8

medicinal chemistry

Question 9

uses physical organic principles to understand the interaction of small molecular displays with the biological realm

Answer 9

working definition
medicinal chemistry
Paul Erhardt (2002)

Question 10

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

Answer 10

med chem

Question 11

2 phases of drug design

Answer 11

1- basic concepts of drugs, receptors, & drug-receptor interaction
2- clinical application of concept of drug interactions

Question 12

basic concepts of drugs, receptors, & drug-receptor interaction
3 steps

Answer 12

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

Question 13

clinical application of concept of drug interactions
3 approaches

Answer 13

1- manipulation of the body’s endogenous control systems
2- manipulation of body’s endogenous macromolecules
3- inactivation of harmful exogenous substances

Question 14

stages of drug discovery, design & development

Answer 14

1- drug discovery
2- drug design
3- drug development

Question 15

stage 1
Target ID & Validation
choosing a disease

Answer 15

-diseases where there is a need for new drugs
-prevalent disease
-economic factors
-orphan drug

Question 16

stage 1
Target ID & Validation
*choosing a drug target

Answer 16

-target specificity & selectivity
-multitarget

*the chosen target may over time lose its sensitivity to the drug

Question 17

stage 1
Target ID & Validation
identify a bioassay

Answer 17

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

Question 18

Ames test

Answer 18

-in vitro
-salmonella typhimurium

Question 19

hERG test

Answer 19

both in vivo & in vitro

Question 20

acute toxicity tests on mice

Answer 20

in vivo

Question 21

lead discovery

Answer 21

-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

Question 22

lead discovery
chromatography

Answer 22

isolation and purification

Question 23

lead discovery
X-ray crystallography
NMR spectroscopy

Answer 23

structure determination

Question 24

-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

Answer 24

high throughput screening

Question 25

- 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

Answer 25

NMR spectroscopy

Question 26

nuclear magnetic resonance spectroscopy

Answer 26

NMR spectroscopy

Question 27

-pharmaceutical companies have prepared thousands of compounds -they are stored in the freezer, catalogued & screened on new targets as these new targets are identified

Answer 27

synthetic banks

Question 28

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

Answer 28

computer assisted drug design

Question 29

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

Answer 29

serendipity

Question 30

yew tree taxus brevifolia

Answer 30

paclitaxel

Question 31

Qinghao artemisia annua L.

Answer 31

artemisinin

Question 32

poppy papaver somniferum L

Answer 32

morphine

Question 33

penicillium notatum

Answer 33

penicillin

Question 34

horse shoe crab limulus polyphemus

Answer 34

Limulus Amebocyte Lysate (LAL)

Question 35

epipedobates tricolor

Answer 35

epibatidine

Question 36

marine cone snail conus geographus

Answer 36

ziconotide

Question 37

gila monster heloderma suspectum

Answer 37

exenatide

Question 38

brazilian viper bothrops jararaca

Answer 38

teprotide

Question 39

sulfonamide is converted into

Answer 39

tolbutamide & chlorothiazide

Question 40

warfarin to

Answer 40

tipranavir

Question 41

lead optimization goals of drug design

Answer 41

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

Question 42

structure activity relationships (SARs)

Answer 42

-part/group of the ,olecule important to biological activity -identification of pharmacophore *important binding groups w/c are required for activity

Question 43

drug optimization goals

Answer 43

-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

Question 44

drug optimization strategies

Answer 44

-variation of substituents -extension of the structure -chain extension/ contraction -ring expansion/ contraction -ring variations -ring fusions -simplification of the structure -rigidification -conformational blockers

Question 45

isosteres

Answer 45

atoms or group of atoms w/c have the same valency (# of outer shell electrons) & w/c have chemical or physical similarities

Question 46

bioisoteres

Answer 46

biologically-active compounds containing an isostere

Question 47

toxicity testing

Answer 47

-acute -subacute -chronic -reproductive toxicity & teratogenicity -carcinogenicity -mutagenicity -investigative toxicology

Question 48

clinical development phase 1

Answer 48

20-100 volunteers

Question 49

clinical development phase 2

Answer 49

100-500 volunteers

Question 50

clinical development phase 3

Answer 50

1,000-5,000 volunteers

Question 51

phase 4

Answer 51

post approval

Question 52

out of every 10,000-15,000 new compounds identified during discovery

Answer 52

-5 are considered safe for human testing -1 of these compounds is typically approved as a marketed drug