Foundation Exam II - Lapinsky

functional groups

a specific arrangement of atoms with predictable chemical reactivity and interaction with biological targets

proteins

the most dominant drug target class

electron donating groups

push electron density toward the conjugated system

hyperconjugation

a type of stabilization that occurs when electrons in a neighboring sigma bond delocalize into an adjacent empty or pi orbital

electron withdrawing groups

pull electron density away from the conjugated system

acidic functional groups

functional groups that lose their H

basic functional groups

functional groups that accept H atoms

conjugation

the continuous overlap of adjacent p orbitals that allows electron density to be delocalized across multiple atoms

- EDG

- resonance

if the atom directly attached to an aromatic ring or a double bond contains a lone pair of electrons, the substituent is an ______ group via _______ effect

alkyl groups

functional group that don't contain lone pairs next to an aromatic ring or double bond but acts as a EDG via hyper conjugation

- EWG

- inductive

when FG with lone pairs are not directly attached to an aromatic ring or double bond, they act as an _________ group via _________ effect

- EWG

- resonance or inductive

when an atom is directly attached to an aromatic ring or double bond, but does not contain a lone pair of electrons, it acts as a ________ group via ________ effect

resonance/resonance effect

electron donation or withdrawal through pi bonds or lone pair electrons

resonance

resonance or inductive effect: requires conjugation

resonance

resonance or inductive effect: stronger electronic effect

resonance

resonance or inductive effect: persists across a conjugated system

induction/inductive effect

electron donation or withdrawal through sigma bonds due to differences in electronegativity

inductive

resonance or inductive effect: does not require conjugation

inductive

resonance or inductive effect: weaker electronic effect

inductive

resonance or inductive effect: rapidly decreases with distance

- chemical reactivity

- drug stability

- effects on nearby functional groups

what are the consequences of electronic effects in medicinal chemistry

acidic hydrogens

H in a structure that is most likely to be released

true

T or F - the H attached to a triple bond is more acidic than the H attached to a single bond

basic nitrogen atoms

N atoms that is part of a double bond in a ring and has a lone pair; nitrogen atoms that accept a H

true

T or F - a N atom must have a lone pair to be basic

nucleophile

electron-rich chemical species that donate electron density to electron-deficiency reaction centers

nucleophilic functional groups

FGs that contain a nucleophilic atom within an electron-rich chemical species that donates a lone pair of electrons to an electrophile

nucleophilic atom

an electron-rich center within a molecule or ion that acts as a Lewis base by donating a pair of electrons to an electrophile, forming a new covalent bond

Nucleophilicity

Tendency of a species to donate electrons

electrophile

an electron-poor chemical species that accepts electron density from an electron-rich reaction center

electrophilic functional groups

FGs that contain an electrophilic atom within an electron-poor chemical species that accepts a lone pair of electrons from a nucleophile

electrophilic atom

an electron-deficient center in a molecule or ion that seeks electrons, acting as a Lewis acid by accepting an electron pair to form a new bond

electrophilicity

Tendency of a species to accept electrons

electrophilic warhead

reactive chemical functional group incorporated into a small molecule inhibitor designed to form a covalent bond with a specific, often non-catalytic, nucleophilic amino acid residue (such as cysteine, lysine, tyrosine, serine, or threonine) on a target protein.

hydrogen bond donors

atoms that have a H atom attached to electronegative atom to contribute to H bonding

hydrogen bond acceptors

atoms that have a lone pair on an electronegative atom to contribute to H bonding

true

T or F - if a lone pair is involved in resonance, it is NOT available as a HBA

aromaticity

the unusual thermodynamic stability that arises when a cyclic, planar, fully conjugated system contains pi electrons, allowing continuous delocalization of electron density around the ring

false

T or F - if a lone pair is required to maintain aromaticity, those lone pair electrons can act as a HBA

lipophilicity (lipid solubility)

The ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents

hydrophilicity (water solubility)

The ability of a substance to dissolve in water or polar solvents

lipid-soluble FGs

FGs that cannot ionize and cannot participate in H bonding

water-soluble FGs

FGs that have the ability to ionize and form H bonds

acidic or basic

FGs that are capable of ionization are either _______ or ________ in nature and can provide a negative or positive charge to increase water solubility

balancing H20 and lipid solubility

what is drug design almost always based on

H20

H20 or lipid soluble: dissolution

H20

H20 or lipid soluble: aid in drug distribution in blood and extracellular fluids

H20

H20 or lipid soluble: poor penetration through the BBB when high

H20

H20 or lipid soluble: cleared rapidly

poor

if a drug is too hydrophilic, it has ______ membrane permeability

lipid

H20 or lipid soluble: can cross membranes during absorption

lipid

H20 or lipid soluble: drug penetration into cells, tissues, membranes

lipid

H20 or lipid soluble: requires metabolic conversion to polar metabolites in the liver

dissolution

when a drug is too lipophilic, it has poor _______ and increased toxicity risk

enzymes

catalyze chemical reactions (40-45% of protein drug targets)

receptors

participate in signal transduction (30-35% of protein drug targets)

ion channels

control ion flow (5-10% of protein drug targets)

transporters

move substrates across membranes (5-10% of protein drug targets)

ionic bond

A chemical bond resulting from the attraction between oppositely charged ions.

hydrogen bond

a reversible, non-covalent electrostatic interaction between a H atom that is covalently bonded to an electronegative atom and 1 lone pair of electrons on another electronegative atom

equilibrium

pharmacology lives at __________

FGs

every single drug has a given PK/PD profile that is directly dictated by the _____ of the drug molecule

PD

PD or PK: what the drug does to the body

PD

PD or PK: driven by binding of functional groups

PD

PD or PK: the central theme is biological response

PD

PD or PK: focused on drug-drug target interactions and effects

PD

PD or PK: happens at the site of action

PD

PD or PK: clinical manifestation by therapeutic effects and side effects

PD

PD or PK: fails when the drug binds to the wrong drug target or very weakly bind

PD

PD or PK: determined by binding affinity, efficacy, drug target selectivity

PK

PD or PK: what the body does to the drug

PK

PD or PK: driven by ionizable FGs, lipophilicity, and metabolic FGs

PK

PD or PK: central theme is drug exposure over time

PK

PD or PK: focused on drug movement and fate in the body

PK

PD or PK: happens throughout the body

PK

PD or PK: clinical manifestation through drug onset, duration, and dosing frequency

PK

PD or PK: fails when the drug never reaches or stays at the drug target

PK

PD or PK: determined by ADME

- propranolol: two rings

- atenolol: one ring + amide

what is the structural difference between propranolol and atenolol

lower, higher

atenolol has an amide while propranolol does not. this means atenolol has a ______ lipophilicity and ________ solubility

lower, lower

atenolol has an amide while propranolol does not. this means atenolol has ______ BBB penetration leading to ________ CNS side effects

polar

the differences between atenolol and propranolol show that chemists can tune H20 vs lipid solubility by adding or removing _______ FGs without destroying the ability of the drug to bind to its desired target

PK/PD profile

Relationship between pharmacokinetics and pharmacodynamics that every drug has

route of administration

the differences between penicillin G and V show how chemists can change the _________ with FGs

electron withdrawing

Penicillin V has an addition of an ether oxygen compared to penicillin G. this increases the __________ characteristics via an inductive effect

increases acid stability in the stomach and allows the drug to survive gastric conditions

Penicillin V has an addition of an ether oxygen compared to penicillin G. why does this allow Penicillin V to be given orally

pharmacophore

the minimal set of FGs and their 3D arrangement in space required for a drug to bind to its biological target and produce a pharmacologic effect

prodrug

a pharmacologically inactive compound that is metabolized in vivo to release active drug (advantageous for oral administration)

ability of drug to bind to drug target

enalaprilat is ionized while enalapril is unionized. this example explains chemists ability to change ___________

mask/remove

enalaprilat is ionized while enalapril is unionized. this explains how some FGs within a drug are required to interact with a drug target. therefore, chemists can ____________ these FGs to abolish drug activity

it does not release until it gets where it needs to go

why are prodrugs advantageous for oral administration

mechanism of action

aspirin has an addition of an acetyl group which causes covalent inhibition. this difference between aspirin and ibuprofen shows the ability of chemists to change __________

longer

aspirin binds covalently while ibuprofen binds noncovalently. this means that aspirin has a ______ duration of action than ibuprofen

reversible inhibition

inhibitor bonds noncovalently to the active site and prevents substrate from binding

irreversible inhibition

inhibitor binds covalently to the active site and prevents substrate from binding

covalent bond

A chemical bond that involves sharing a pair of electrons between atoms in a molecule; irreversible in drug nature

covalent drug target modification

a drug discovery strategy where a pharmaceutical agent forms a lasting covalent bond with a specific amino acid side chain in a target protein

noncovalent bond

Chemical bond in which no electrons are shared. are relatively weak, but they can sum together to produce strong, highly specific interactions between molecules. Examples are hydrogen bonds and van der Waals interactions.

non-covalent drug target modification

involves reversible, weak intermolecular forces—such as hydrogen bonds, electrostatic interactions, van der Waals forces, and hydrophobic effects—that allow a drug molecule to bind to a target

route of administration and elimination

morphine has OH while codeine has OCH3. this example shows how chemists can change the ______________ and ___________