Exam 3 Flashcards
True or False: most drugs on the market are large biologics.
False. Most drugs are small organic molecules(>80%), but biologics are on the rise.
Major sources of drugs
-natural extracts
-natural products-pure molecules isolated from nature
-synthetic drugs
-new drugs from existing drugs
-Synthetic chemical libraries
-natural product libraries
-rational drug design
Nature as the first source of drugs
-almost exclusivly from plants
-many drugs isolated: morphine, quinine, colchine but they were unoptimized for human use(toxic)
-often very large and complex molecules, more rings
synthetic drugs
-carbon source is petroleum
-often much simpler than natural products
-ex) aspirin, chloral hydrate, chloroform, ether
True or false: natural products tend to be larger and more polar molecules than synthetic molecules.
True. Synthetic libraries are often too conservative in their structural properties(Lipinski’s rule of 5)
New drugs from existing drugs
-one drug is structurally modified to make another with a different effect
-ex)antimalaria drug->antihistamin –> Antipsychotic
Screening Corporate Chemical Libraries
-Bayer begins program screening dyes for antimicrobial activity based on Gram’s dye and the discovery of salvarsan
-discovered red dye, Protosil, protects mice from strptococcus
-Protosil is converted into its active metabolite sulfaliamide(antibiotic)
Screening Natural Product COllections
-Paclitaxel discoved as anti cancer drug when screening plant extracts
High Troughput screening(HTS) of chemical libraries
-trial and error approach by using huge libraries to test each molecule againist a validated drug target or organism
WHat is required for a good high throuput screen(HTS)?
-robust assay that asses validated drug target
-assay must be statistically sound
-rapid and inexpensive to assess many molecules
-variety of potentially active substances
-molecule should be slightly water soluble and not prone to aggregation
Rational drug design
-using knowledge of drug target structure or enzyme mechanism to discover molecules that bind to the target
-ex) HIV protease inhibitors
-ex) carbidopa to treat parkinson’ss desease
How does carbidopa work?
Inhibits AADC which converts L-DOPA into dopamine. This allows for more L-DOPA to cross the BBB and be converted into dopanine which can be used for signaling.
Cisplatin
-anti cancer drug
-inhibits cell division
-hydrolysis from Pt electrode
-elongation of mititic spindles
How much does it cost to develop a new drug?
-$2 billion
->10 years
Lead optimization
-optimizes drug to give important attributes
Characteristics of a good drug
-oral bioavailability: water soluble but also small and lipophillic
-chemically stable
-chemically unreactive: avoid immune response
-metabolically stable
-pharmacologically specific
-potent but not too potent
-good toxicity profile
-inexpensive to manufacture
reasons for failuers of drug candidates
-problems with efficacy and toxicity
ionic(charge-charge) interaction
-ions are solvated by water which competes the interaction
-energy is proportional to 1/Dr
Interaction between two charges species
dipole and induced dipole Interactions
-Can be permant or temporary
Induced by random fluctuation in electron density in a non polar group
London Dispersion/ Van der Waal interactions
-optimal distance between two atoms that is energetically favorable
-significant amount of binding energy if atoms are close
-explains importance of “fit” between drug and it’s protein target binding site
Hydrogen bonding interactions
-between H atom(attached to N, O) and another oxygen
-strongest when linear
-water can solvate polar groups via H-Bonds
-protiens use H bonds to fold into secondary and tertiary structures
How does vancomycin work?
-antibiotic
-clamps down on terminus end of peptodogylcan
-H-bond is key to binding(amide is needed. when replaced with ester, binding is weakened 1000x)
cation pi-interactions
-share pi cloud
-aromatic rings are stacked
non-covalent interaction between electron rich pi system and nearby hard metal cation or ammonium
How does acetylcholinesterase bind?
-through cation pi interactions
-aromatic rings of Try-84 and ammonium in achetylcholine
entropy
-measure of uncertantity/probability
-number of microstates available
-ex) more translational and rotational freedom
Hydrophobic effect
-placing nonpolar molecules in water is energetically unfavorable
-oil reduces motion of the water because of noncalvealent interations
-restriction of motion reduces entropy of the system(entropic cost)
True or False: binding if the drug with the drug target is often favorable and the release of water is unfavorable.
False. binding is unfavorable but the release of the water is what makes the reation energetically favorable.
Log P values
-measure used to determine hydrophobicity
-higher value=more lipophillic
what is a pi value?
pi values=log P
log D
-for molecules that are ionizable
-pH dependent
-at pH where molecule is neutral, log D=log P
The main target of drugs
-75% proteins
-21% pathogen protein targets
True or false: most small molecule drugs target protein receptors such as G coupled receptors, ion channels, and nucleur receptors
true
Agonist
induce the proper conformational change in their target receptor that triggers downstream signaling events
Antagonist
inhibit conformational change due to steric clash
partial agonist
mimics the acivity but plateaus at a lower level
Inverse agonist
has the opposite activity of the agonist
competitive antagonists
-shift activity curve to the right
-takes more agonist to get full effect
Noncompetitive antagonist
-affect binding and activity and prevent agonist from achiving full effect by binding at different site on protein
therapeutic index
-want to limit human toxicity while achiving therapeutic effect
-goal is to achieve a wide therapeutic index
true or false: full receptor occupancy is required for maximum activity
False. there are enzymes that amplify the signal
Racemic mix
1:1 ration of each enatiomer
How are single enatiomers formed?
-use enatiomerically pure starting materials(inefficient, old tech)
-diasteromeric salts
-enzymes
-synthetic chiral catalysts
-chiral chromatography
Diasteriomeric salts
-add a single enatiomer of a chiral acid to resolve a mixture of amine bases, vice versa
-only works with amine bases and carboxylic acids
-salts are then seperated by solubility
Enzyme catalysts
-esterases, reductase, asnd other enzymes are often able to distinguish between enatiomers and creat single enatiomers
-often involving aqueous phase and organic phase
Synthetic chiral catalysts
-act like enzymes in that they bind the starting molecule and modify it to produce mostly one enatiomer
-must use single enatiomer of either D or L-tartrate
-forms a metal schafolding and chiral catalytic binding pocket
Monsanto
-anti parkinson’s drug
-uses chiral phodium catalyst to hydrogentat the alkene
-makes enatiospecific route to give L-DOPA
-example of a synthetic catalyst
Chiral chromatography
-single enatiomer is attached to polymer or silica beads
-one enatiomer interacts more tightly via non covalent interations
-expensive and not practical large scale
synthetic biology
-use of recombinand DNA tech to create GMOs for the synthesis of novel products
-sysnthesis of bioactive molecules or their precursors
Chiral center unstability
-some chiral centers are not stable in vivo
-racemization is catalyzed by base(phosphate, amino acids) and protiens(human serum albumin
bioactive conformation
drug molecules that have flexibility due to rotatable bonds can have different bound conformations
-the drug structure when it binds to the target complex is the bioactive conformation
conformational restriction
-uses cross linkers to restrict conformation
-“pre-pays” entropic cost before binding step
Why do natural products contain many rings?
-constrain atoms and limit the number of possible conformations
-improve binding affinity (by reducing entropy loss upon binging)and specificity to the target(rigid molecule)
induced fit
ligand induces a conformational change in the protein
-ligand concentration independent
global minimun conformation
-lowest energy conformation
-usually free of steric hinderence
risks of conformational restriction
-might restrick the molecule in a non binding conformation but this has been perfected by nature
ADME(T)
-absorption
-distribution
-metabolism
-excretion
-toxicity
Lipinski’s rule of 5
-no more than 5 H-bond donars
-less than 10 H bond acceptors
-less that 10 rotatable bonds
-MW<500 daltons
-Log P less than 5
True or false: approved oral drugs always follow Lipinski’s rule of 5.
False. getting a little larger and more complex.
-MW and #rotatable bonds has increased
-LOG P and #HBDs has stayed constant
Does cyclosporine follow Lipinski’s rule of 5?
-NO, because of intramolecular interactions
-3 intramolecular H bonds which sheils polar groups
Do CNS drugs generally follow Lipinski’s rule?
yes, because molecules need to be smaller(<350_ and less polar
active transport
-trans membrane protein pumps/channels
-complete saturation=rate limiting
passive diffusion
-high conc to low conc
-no rate limiting step
Enterocyte
transporter between blood and GI
Hepatocyte
transporter between blood and the bile
Relationship between Log P and permeability
-positive correlation between lipophilicity and passive diffusion
Relationship between log P and BBB passage
-CNS bioavailability requires neutral species for passive diffusion
-above the trend line: active transport
-below trend: efflux pumps
isosteric substitution
-the process of replacing groups of molecules so that it still has similiar properties
-can be done with small groups of atoms, whole rings, an bioactive functional groups
molecular mimicry
-replacements that have very similiar steric properties and involve single atom substitutions
-this sometimes significantly changes drug properties
Non classical biosteric replacments
-replacement has widly different steric properties but it retain properties such as polarity, pKa that are important to retain bioactivity
Cyclic bioisosteres
-mimic carbonyl containing groups as well as pKa and other properties
-But rigity of the ring can induce risk because it is conformationally restricted
Positive aspects for Me-too drugs
-claim to improve ADMET or specific issues
-sometimes have new activities
-can compete with first drug to drive down prices
Negative aspects of Me-Too drugs
-use up resources that could be spent on drug for mor pressing diseases
-minimal additional benefit
-marketing may be exaggerated
-drive up price by delaying entry of generics
Deuterium substitution
-form of isotopic substitution
-prediction was that binding would be identical but this may not be true
-Deuterium has slightly shronger and shorter bond that is kinetically slower to break
kinetic isotope effect
the slower rate of C-D bond breaking vs C-H
-useful if we want to slow down metabolism
antimetabolite
-substrates that block vital metabolic pathways
Multisubstrate analog inhibitors
-reversible inhibitor
-derive binding energy by thethering multiple substrates in one molecule-pre pay entropic cost by freesing the translation of the substrates
transition state analogs
-reversible inhibitor
-derive binding energy by mimicking high energy reaction intermediates and/or transition states
Affinity labels
-irriversible labels
-substrate analogs specific for enzyme active site and contain highly reactive electrophillic group
Mechanism based inhibitors(suicide substrate)
-irreversible
-substrate is converted to a reactve species by the action of the target enzyme
Sulfanilamide
-example of an antimetabolite
-alternative substreate in folic acid biosynthesis
-competes with PABA
6-mercaptopurine(6-MP)
-antimetabolite
-substrate of purine salvage pathway
-end in pathway toxicity and cell death
