CHEM 377: Drugs and Poisons Final Exam

Structure Activity Relationship

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

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

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

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)

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)

chain extension/contraction for epitopes

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

ring expansion/contraction

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

aromatic ring variation

changing the aromatic ring, usually making it a pyridine

ring fusion

adding a fused ring, usually 5 or 6 membered ring

simplification

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

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)

rigidification

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

conformation blockers

sterically prevent a rotational conformation that is less favorable

magic methyl effect

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

multi target drugs

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

hybrid drugs

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

scaffold hop

same active groups, different scaffold: patent busting and companies

optimization of promiscuous drugs

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

optimizing polarity

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

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)

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)

metabolic blockers

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

group shift

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

aromatic ring variation

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

introduce a metabolically sensitive group

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

self destruct drugs

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

targeting tumors

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

targeting GI tract

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

targeting peripheral nerves

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

targeting membrane bound proteins

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

reducing toxicity

remove toxicophores

toxicophores

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

prodrug

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

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

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

prodrug-mask toxicity

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

prodrug-Lower solubility in blood

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

prodrug-Improved water/blood solubility

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

prodrug-target drug delivery

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

prodrug-increase stability

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

prodrug-activated externally

"sleeping agents" activated by UV/light, etc

who chooses disease targets?

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

Key facets of picking a drug target

Species selectivity, protein selectivity, organ selectivity

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

bioassay

pre-clinical trials; studies not in humans

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

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

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

medical folklore ((pro/cons))

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

Me too/me better

drugs from diffferent companies looking at same target

SOSA

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

modifying original ligands

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

combinatorial and parallel synth

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

in silico (virtual) screening

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

serendipity

chance. Yay!

fragment-based discovery

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

epitopes

small molecules that interact with different parts of a binding pocket

rule of 3

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

Aconitine

Source: Plants in the X genus (Wolfsbane)

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

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)

Aconitine Structure

Batrachotoxin

Source: Poison dart frogs (Genus: Phylobates)

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

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)

Batrachotoxin structure

Coniine

Source: Poison hemlock (Xmaculatum) and Yellow Pitcher plant

Death caused by asphyxia due to inability to breathe.

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

Coniine Structure

Tetrodoxin

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

Produced by symbiotic bacteria

Tetrodoxin Mechanism

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

Tetrodoxin structure

Sarin

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

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

Sarin Mechanism

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

Sarin structure

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.

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.

Ricin structure

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

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.

Amatoxin structure

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.

Mustard Gas Mechanism

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

Mustard Gas structure

Zyklon B

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

Acute exposure leads to cardiac arrest.

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.

Zyklon B structure