Exam #1 Flashcards
What is Medicinal Chemistry?
The chemistry of drugs and their targets
-Discovery
-synthesis
-mechanism
-Stability and metabolism
John Proctor-Fr of Pharmacy
What is the relevance to pharmacy?
- foundational scientific knowledge: the chemistry of how drugs work.
- increasing importance in personalized medicine (if people carry mutations)
- inform therapeutic evaluations, recommendations, patient counseling for safe and effective use of drugs.
- clinical experts
Where do drugs come from?
Natural products
Rational Design
-Ligand-based drug design
-Structure based drug discovery
High-throughput Screening
-chemically diverse libraries
-fragment-based drug design
-computational screening
Natural Products
Plants/ microbes/ animals
Ligand based
Takes drug and target and creates drug target complex, that creates a physiological effect.
-focuses on the ligand: which part of the ligand improves binding to the target without having to know anything about target
ex: finding out if you have a right or left-handed glove by seeing which hand fits into it
Structure based
Based on structure of the target
ex: looking at glove and seeing that right or left hand goes in
Screening
Testing a large number of structurally diverse chemical compounds in a rapid manner to find compounds that bind to the target or have other properties.
-testing for binding/ inhibition effects
Mechanism of how drugs work
kd= (target)(drug)/ (target:drug)
the lower the kd the tighter bond it has to the target; higher drug affinity.
the more negative the Delta G= the more favorable/ strong it binds to the target.
The lower the IC the more potent
-The lower the IC, the lower the Kd
the lower the Emax the less effective
Structure-Activity Relationships (SAR)
Changes in chemical structure impact biological activity
-SAR: Structural activity relationship: enables the improvement to make drugs that bind more potently and selectively to targets.
ADME-Tox
A: Absorption-movement of drug into the bloodstream
D: Distribution- reversible transfer of drug from one location to another in the body
M:Modification- biochemical modification of drug structure, usually by enzymes
E: excretion- elimination of drugs and their metabolites from the body
Tox: Toxicity: damage to the body caused by the drug
Molecule Depictions
Molecular: C3H10
Structural: CH3(CH2)2 CH3
Bond-line drawing
line drawing
Combination
Typical bonding patterns for
H
O
N
C
Halogens
P
S
H=1
O=2 bonds; 3 bonds it is +
N=3; 4 bonds it is +
C=4
Halogens=1
P=3 or 5
S=2, 4 or 6; 3 bonds it is +
Tautomerization
Atom connectivity is different (if you lose or add an H)
-Need to use equilibrium arrows ( two arrows)
-Each structure represents a different species in equilibrium with. The other.
Resonance
-Atom connectivity does not change
-not separate species, the molecule is a combination of all the resonance forms.
-use resonance arrow ( double-sided arrow)
Partial charges
-suggest where a reaction can occur(where a nucleophile can attack)
-relevant for drug stability, metabolism and sometimes mode of action.
Bond Dipoles
-pulls towards what is most electronegative, the carbon with the most dipole moments is where the Nu will most likely attack.
Direction of arrows
-always goes from electron source to electron sink.
nucleophiles to electrophiles
Retrosynthetic: conceptually breaking it into parts that you know how to assemble by organic chemistry.
Alcohol
-can help bind to target due to H-bonding
-increases water solubility
-can be a site for metabolic transformations.
-Alcohol side chains can H-bind with drugs, water or other parts of the protein
Ser and Thr
Halogens
F is about the same as H (smallest)
Cl
Br is about the same as CH3
I
CF3 (largest)
Replacement of H with a halogen introduces a larger group (has no effect if it is F though)
-Halogens on alkanes can be reactive
-Halogens on aromatic rings withdraw e density from the ring, making it less likely to be metabolized.
VDW attraction increases with # of electrons.
-few drugs contain halogens, especially F, Cl and Br, due to the instability of the carbon-iodine bond.
-most halogens are on aromatic rings, which increases hydrophobicity and blocks metabolism
Thiols
Comparable to alcohols, but have different properties
-Sulfur is larger and more polarizable than oxygen
- interactions are mainly VDW ( h-bonding, not a MAJOR factor for side chai)
-does not increase water solubility.
Reactivity
-Oxidation can occur in air, or catalyzed by enzyme; can form covalent bonds between drug and itself or drug and target.
if it is off target, then it is toxic
-reduction is catalyzed by enzymes
thiols are not common functional groups.
Ethers
can be linear or cyclic
Ethers are less hydrophobic than CH2 due to ability to H-bond but more hydrophobic than ROH
chemically stable, except when they are strained (epoxide)
metabolism leads to oxidation that forms an unstable intermediate that breaks apart.
No Amino Acids
Thioethers
More acute angle
More hydrophobic than ethers ( because S cannot H-bond)
mainly VDW
can be Oxidized
Phenols
Hydrophilic due to ionization and H-bonding
VDW+H-bond+ ionization
pka=10
More water-soluble than OH due to ionization.
It is also wayy more acidic than PH due to resonance stabilization.
Can be oxidized in the air or metabolically to make quinone electrophiles
Can be metabolically conjugated through methylation or sulfanation
Tyr
Amines
pka=10.52
Equilibrates: neutral form can cross membrane, positive form is water-soluble
H-bond donor and acceptor
Can serve as a nucleophile (neutral form) or base (catalyze deprotonations)
reactivity:
-Oxidized, methylated, or de-alkylated
Lys
ARG and HIS ( not amine but just basic)
