CHEM 377: Drugs and Poisons Final Exam

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85 Terms

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Structure Activity Relationship

which groups are responsible for binding/effect of drug? Can be explored with isosteres

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isosteres

synthesized alternative structures which maintain similar group size but may create a change in electronic availability, e.g. change in H bonding or electronegativity

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bioisosteres

synthesized alternative structures which maintain similar group size but may create a change in electronic availability, e.g. change in H bonding or electronegativity but have similar biological activity e.g. similarly metabolized as original structure

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substituent variation

keeping structure mostly the ssame but varying position or length (e.g. lengthening a carbon chain or moving the group around the phenyl ring)

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structure extension

adding more groups to reach a new area in a binding pocket (e.g. make another H bond or reach another vdw region)

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chain extension/contraction for epitopes

recall epitopes are linked by a carbon chain; changing the length of the chain

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ring expansion/contraction

making a ring larger or smaller (usually 5-7 are stable)

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aromatic ring variation

changing the aromatic ring, usually making it a pyridine

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ring fusion

adding a fused ring, usually 5 or 6 membered ring

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simplification

getting rid of any nasty middle parts that are difficult to synthesize and keeping the active groups

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simplification of chirality

getting rid of any chirality by changing the molecule to be symmetric (evening out groups, changing the chiral carbon to a nitrogen)

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rigidification

use double bonds, esters, amides, or ring formation to make sure certain groups have a certain position.

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conformation blockers

sterically prevent a rotational conformation that is less favorable

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magic methyl effect

conformation blocking with just one methyl! One methyl can make big changes

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multi target drugs

...have multiple targets. Chain 2 drugs together (hetero/homo-dimeric)

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hybrid drugs

2 drugs in a combined molecule since og drugs were similar enough scaffolds to combine

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scaffold hop

same active groups, different scaffold: patent busting and companies

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optimization of promiscuous drugs

drug may be selective for two target proteins, optimize its interactions with just one

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optimizing polarity

change side groups to make more polar/change pKa. -->use bioisosteres

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Steric Shield

method of metabolism resistance. Involves putting a group in the way of metabolic enzyme pathway (e.g. tBu by an ester to prevent hydrolytic esterase activity)

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Bioisostere electronic effect

using bioisostere may prevent recognition of the motif, i.e. cannot be broken down by enzyme because looks different electronically (e.g. replace beta carbon in a an ester with a nitrogen to make resonance structure which would resist metabolism)

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metabolic blockers

changing the group to something that can't be metabolized (i.e. a fluorine isostere)

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group shift

method of metabolism resistance. change position of a metabolically active group

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aromatic ring variation

metab. resistance: change to a pyridine or add an EWG like CN)

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introduce a metabolically sensitive group

...add a group like an exposed CH3 or a small unhindered ester

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self destruct drugs

drug self destructs regardless of metabolic enzymes (e.g. sensitive to temperature and metabolizes to

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targeting tumors

attach drug to a.a. or nucleic acids, or antibodies for tumor

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targeting GI tract

make drug very polar/ionic bc then cant enter cell membranes

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targeting peripheral nerves

increase polarity a little bit (but not too much since BBB is still kinda greasy

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targeting membrane bound proteins

add a carbon chain - hydrophobic, will nestle into membrane and intxt w membrane proteins

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reducing toxicity

remove toxicophores

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toxicophores

groups that are toxic or metabolized to toxic compounds [ know some examples or toxicophores]

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prodrug

drug not in active form when first ; metabolism puts it in active form

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prodrug-improve membrane permeability

more lipohilic at first, then more polar after metabolism. E.g. ester to mask Coo-, N-Methyl to mask NH) KNOW EXAMPLES

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prodrug-prolong activity

A) Drug as a leaving group; e.g. interacts with gluthathione. B)lipophilic tether with an ester: slow release from fat tissue

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prodrug-mask toxicity

e.g. that hydroxyl group causes stomach bleeding; hide with an ester

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prodrug-Lower solubility in blood

why? Reduce bad taste, slower release (accumulate in fat cells); e.g. add hydrophobic chain

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prodrug-Improved water/blood solubility

too greasy, all goes to fat; increase blood solubility (e.g. add amino acid or phosphate)

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prodrug-target drug delivery

put on a group to be metab by bacteria or viral enzymes or low pH (in stomach or bladder)

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prodrug-increase stability

e.g. beta lactams interupted from being attacked by intermolecular nucleophile by closing off with a ring structure

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prodrug-activated externally

"sleeping agents" activated by UV/light, etc

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who chooses disease targets?

companies pick chronic disease in wealthier countries. Researchers/humanitarians pick diseases in poorer countries

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Key facets of picking a drug target

Species selectivity, protein selectivity, organ selectivity

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multipathway and multitarget drugs in drug design

drugs may interact with different pathways, or interat with multiple targets; consider these also during design (e.g. off target interactions) different pathways in the cell can counteract efficacy of drugs

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bioassay

pre-clinical trials; studies not in humans

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in vitro (pros/cons)

pros: cheap, 1,000s to 10,000s scale, fewer variables, can find some toxicity, less controversial, many ways to measure; cons: no ADME data

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in vivo (pros/cons)

pros: Adme data, closer to humans, can indicate more toxicity; cons: not automated, more controversial, expensive, smaller samples 10s-100s scale, doesn't model human enzymes perfectly in metabolism

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natural product screening(pro/cons)

pros: lots of varied structures, potent, orgs use chemicals for defense; cons: hrd to isolate, small quantities, difficult to synthesize

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medical folklore ((pro/cons))

pros: can have potent compounds, cons: can give way to quakery and placebos, ineffective, naturalistic fallacy

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Me too/me better

drugs from diffferent companies looking at same target

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SOSA

Selective Optimization of Side Activites; optimize the side effects of an existing drug to make new drug (e.g. warfarin derivatives)

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modifying original ligands

can make an inhibitor, agonist, antagonist (like our drug project)

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combinatorial and parallel synth

can be automated; synthesize a small quantity of 100s-10000s of drugs; shotgun approach

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in silico (virtual) screening

computer simulations, can screen millions, lots of false positives, requires known PDB structure

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serendipity

chance. Yay!

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fragment-based discovery

design little epitopes for different binding pockets, attached with a carbon chain

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epitopes

small molecules that interact with different parts of a binding pocket

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rule of 3

MW<300, HBD<3, HBA<3, logP<3, rot bonds< 3, tPSA<60 A^2 (less than or equal to)

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Aconitine

Source: Plants in the X genus (Wolfsbane)

Death occurs due to cardiac arrest and/or respiratory paralysis.

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Aconitine Mechanism

Mechanism: (Agonist) Locks sodium-ion channels in the open conformation. Depolarizes membrane potenital, the nerves can’t reset.

Source: Plants in the X genus (Wolfsbane)

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Aconitine Structure

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Batrachotoxin

Source: Poison dart frogs (Genus: Phylobates)

Death occurs due to cardiac arrest and/or respiratory paralysis.

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Batrachotoxin Mechanism

Mechanism: (Agonist) Locks sodium-ion channels in the open conformation. Depolarizes membrane potenital, the nerves can’t reset.

Source: Poison dart frogs (Genus: Phylobates)

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Batrachotoxin structure

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Coniine

Source: Poison hemlock (Xmaculatum) and Yellow Pitcher plant

Death caused by asphyxia due to inability to breathe.

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Coniine Mechanism

Mechanism: (Agonist) Locks sodium-ion channels in the open conformation. Binds specifically to the sodium ion channels that respond to acetylcholline or nicotine.

Source: Poison hemlock (Xmaculatum) and Yellow Pitcher plant

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Coniine Structure

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Tetrodoxin

Source: Marine sources: Pufferfish, octopi, squid, horshoe crabs, some flatworms and ring worms.

Produced by symbiotic bacteria

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Tetrodoxin Mechanism

Mechanism: (Antagonist) Blocks sodium ion channels. Nerves unable to signal (loss of feel). Toxic doses cause paralysis of heart and diaphragm.

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Tetrodoxin structure

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Sarin

Source: Based on a pesticide called Tabun. Used by Germans in WW2

Death caused by asphyxia due to inability to control the diaphragm.

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Sarin Mechanism

Mechanism: Irreversible inhibitor of AChE. Leads to buildup of acetylcholine, causing continuous neuron activation.

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Sarin structure

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Ricin

Source: Isolated from Castor beans (X communis). The A-chain of the protein heterodimer held together with a disulfide bond is the active chain responsible for toxicity.

Death occurs by shock and organ failure.

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Ricin Mechanism

Mechanism: A-chain cleaves adenin in 28S rRNA. A structural component of the ribosome needed for function (ribosomal RNA). One A-chain can cleave these adenine residues in 1500 ribosomes per minute.

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Ricin structure

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Amatoxin

Source: Isolated from mushrooms (X, Galerina, and Lepoita) aka death cap or paddy straw. Related compounds: α-Amanitin, β-Amanitin, γ-Amanitin

Death occurs several days after ingestion typically due to organ and kidney failure

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Amatoxin Mechanism

Mechanism: Interferes with the movement of the “bridge helix” in RNA polymerase II. Movement of the bridge is required for translocation. α-Amanitin binding reduces nucleotide rate from several thousand per minute to <10 per minute.

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Amatoxin structure

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Mustard Gas

Source: European chemists in late 1800’s. Germany WWI. Results in bullae (fluid-filled blisters)

Initial effects are intense itching and blistering (chemical burns). Death occurs due to severe burn injuries.

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Mustard Gas Mechanism

Mechanism: Targets DNA. Alkylating properties make them strongly mutagenic (DNA altering) and carcinogenic (cancerous)

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Mustard Gas structure

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Zyklon B

Source: Cyanide-based pesticide. Germany, Jew execution, 1942

Acute exposure leads to cardiac arrest.

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Zyklon B Mechanism

Mechanism: Targets the Electron Transport Chain/ATP Synthesis. Hydrogen cyanide released once canister is exposed to air. Binds the heme in cytochrome c oxidase: Halts electron transport chain.

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Zyklon B structure

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