Random Questions Flashcards
Why do only very few drugs contain furan?
Furan (5 membered “O” heterocycle) undergoes CYP mediated metabolism into BDA
BDA can react with variety of endogenous molecules including 2′-deoxycytidine, 2′-deoxyadenosine, and 2′-deoxyguanosine in DNA - potential genotoxicity of drugs containing furan
Lipinski’s Rules
- MW > 500
- logP >5
- > 5 H-bond donors (expressed as the sum of OH and NH groups)
- > 10 H-bond acceptors (expressed as the sum of N and O atoms. Note: It is a very simplified rule. This approach to counting does not always predict the actual number of h-bond acceptors correctly)
- Antibiotics, antifungals, vitamins, and cardiac glycosides are the exception because they often have active transporters to carry them across membranes.
It is highly likely (>90%) that compounds with two or more of these characteristics will have poor absorption properties.
DESIRED TPSA to be able to cross CELL MEMBRANE
TPSA < 140 Angstroms
LESS THAN 140
DESIRED TPSA to be able to cross BBB
TPSA < 90 Angstroms
LESS THAN 90
Huckel’s Rule
4n + 2pi
= 2,6,10,14,18 pi electrons
to be AROMATIC
Heteroatoms in order of Polarity
N is most POLAR
N > O > S
Heteroatoms in order of Lipophilicity
S > O > N
S is most LIPOPHILIC
Increasing logP of the heterocycle that contains the atom
Ex.
Thiophene (S) logP = 1.79 > Pyrrole (N) logP = 0.75
pKa trend for basic aromatic heterocycles
More Nitrogens = Less Basic ( lower pKa )
logP
logP = octanol / H2O
Drugs & Bioactive molecules - logP= 1-5
logP=5 >>> 105 parts octanol : 1 part H2O
Saturated 5-mem heterocycles
Structural Properties
Puckered Conformation
NOT FLAT
ex. pyrrolidine
5-membered AROMATIC heterocycles
Structural properties
ALL FLAT
ex. Pyrrole (pka 1-5, weak base)
O/S hetrocycles not considered Acid or base
Unsaturated 5-membered heterocycles
Structural Properties
ALL FLAT
Beta-Lactams MOA
- β-Lactam antibiotics inhibit DD-transpeptidase
- β-Lactam Covalently Bonds to the ester on DDTP
- Irreversible reaction
Factors Affecting Beta Lactam REACTIVITY
-
MORE pyramidal > MORE REACTIVE
- free pair of electrons is conjugated w/ pi electron of C=O bond
-
MORE orbitals of N are sp3 hybridized > MORE reactive
- reduces partial double bond character
- WEAKER the C-N bond > More reactive
- LOWER partial double bond character > More Reactive
Effect of Reactivity of Beta Lactam Antibiotics
Very Reactive - FAST antibiotic effect, ~fast degradation
Moderately reactive - Extended effect, ~slow degradation
Low Reactivity - may NOT inhibit DDTP
instead used for inhibition of Beta-lactamase (cleaves B-lactam)
Responsible for ANTIBIOTIC RESISTANCE
3-mem heterocycle DRUGS
All Reactive due to Ring Strain (rxn w/ nu-)
Steric hinderence = unusually stable
Aziridine Rings –> DNA alkylating agents
VERY REACTIVE, not very selective can hurt your DNA
O-containing 3Rings
NOT ALL are reactive, have to be accessible
S-containing 3rings = No FDA approved drugs
4-mem heterocycle DRUGS
O-containing 4rings = Not all Reactive
Oxetane = NOT REACTIVE
Lactone = REACTIVE
S-containing 4rings = No FDA approved drugs
3/4-membered heterocycles
Structural Properties
- Very RIGID
- The 3- and 4-membered saturated heterocycles ARE NOT FLAT as they are made from sp3 hybridized atoms. This may improve dissolution and solubility.
- 3-membered saturated heterocycles have only one conformer
- 4-membered saturated heterocycles have two “envelop” conformers
3/4-membered heterocycles
effect on DRUG PROPERTIES
Off Target Reactivity > Adverse Rxns & Shortening duration of Action
ex. Alkylating agents > tissue dmg
Beta Lactams > form haptens > Immunogenic response
Chemical Instability > Storage/Formulation/Routes of Administration
Electronic Properties of 6mem Heterocycles
- Aromatic/unsaturated 6mem heterocycles = ALL FLAT
- 6mem Aromatic N-heterocycles = weakly basic
- pKa ~-1 - 6
- 6mem S-heterocycles do not have acidic or basic properties
Factors that help diffusion through a cell membrane
To INCREASE diffusion / slipperiness (k):
HIGHER = logP or logD
HIGHER = HSA
less = H-bond acceptors & donors
lower = MW
lower = SASA / TPSA
SASA
SASA = surface area of a molecule accessible to a solvent (WATER)
INVERSELY RELATED TO PERMEABILITY
Decreasing SASA > MORE PERMEABLE (less water solubility)
The Higher the density of the packing (pi-pi stacking / sp2 vdw interactions)
MORE energy required to disrupt interactions between molecules to achieve dissolution & solubility
MORE difficult for other molecules to get IN BETWEEN
TPSA (Topological polar surface area)
TPSA = surface area of all the polar parts of a molecule (mainly N,O)
INVERSELY RELATED TO PERMEABILITY
DECREASING TPSA > INCREASES SOLUBILITY
HSA
HSA = surface area of all the HYDROPHOBIC parts of the molecule (mostly all EXCEPT N/O)
INCREASING HSA > INCREASES PERMEABILITY
pH effect on H-bond donor/acceptors
pH dependent!
blue = donor
red = acceptor
H-Bond DONORS
Alcohol = 1 (note – has 2 h-bond acceptors on the O)
Amide = 1 (note – has 2 h-bond acceptors on the O)
pyrrole = 1
1*(primary) amine = 2
H-Bond ACCEPTORS
Ketone = 2
Ether = 2
Imine = 1 (nitrogens in aromatic systems as well)
Oxazole = 1
*Sulfur is generally NOT a good H-Bond Acceptor
*Amide nitrogens are NOT Acceptors due to partial double bond/rigidity
*Tertiary 3* amines are generally NOT acceptors due to rigidity
6-membered Heterocycles
Effect on Drug Properties
Saturated & Aromatic 6mem heterocycles (NOT SULFUR) are widely used in drugs.
Saturated & Aromatic 6mem heterocycles are ELECTRON DEFICIENT
-Not as reactive as 5 membered pyrrole/thiophene/furan
Evaluating changes in logP along with TPSA
When actually adding the two molecules, some of the molecule is not being ADDED.
-Less than the actual addition.
SO, logP is used in COMBINATION with TPSA to beter determine permeability of a drug
Order of Presidence
S>O>N
Higher the molecular weight > Higher presidence
*same with naming the molecule
ie. 1,4-thiazepine not 1,4-azethiazepine
Saturated 7-Membered Heterocycles in Drugs
Several Drugs with N/O 7mem heterocycles ie.
tolazamide, azelastine,emadastine,suvorexant
**There are NO DRUGS w/ Sulfur-containing heterocycles
UNSATURATED 7-membered heterocycles
NOT AROMATIC / NOT FLAT
Imino groups within the 7-mem system are BASIC pka~2-4
*For drugs, Replace NITROGEN for SULFUR for STABILITY
Sulfur doesnt have the double-bond side-effect
ex. drugs: Clozapine > Quetiapine / Olanzapine
Solvation and De-Solvation on Drug Receptor Binding
Solvation (solute’s interaction w/ solvant) & De-solvation plays an IMPORTANT role in the binding of drugs to their receptors.
Unbound: ΔGprotein/S + ΔGligand/S + ΔG1solvent1
Bound: ΔGprotein-ligand/S ΔG1solvent2
Veber’s Rules
of NON-TERMINAL single bonds
>10 rotatable bonds = POOR BIOAVAILABILITY
of Rotatable bond =
+
- *saturated ring must have 4 or more carbons*
- *if connected to an aromatic system, do not count the “touching” single bound*
Relationship Between
Rotatable Bonds & Entropy
MORE Rotatable Bonds = GREATER ENTROPY
Greater Entropy = Poor Permeability
*RACE AGAINST TIME, if the correct conformation of the drug doesn’t form in time it will get EXCRETED
•Change in entropy of the drug can be roughly estimated from the loss of rotational degrees of freedom of the drug
Relationship Between
Rate of Diffusion & Molecular Weight
Larger MW = Slower Rate of Diffusion
slower to cross the membrane
RACE AGAINST TIME
Privileged Scaffold Types
Types found in DRUGS (most common)
Types found in Natural Products
Priveledged scaffolds mimic interactions w/ common receptor motifs:
- Alpha-helix
- Beta-turn
- Gamma-turn
- Beta-strand
Why are Priveledged Scaffolds a EXCEPTION to the lipinski’s rules?
ACTIVE TRANSPORT
- Allows our compounds to bypass the LIPINSKI rules
- Has specific means to get absorpbed / pass the lipid bylayer
- Does not have issues with P = KxD/x
Types of Uptake & Efflux Transporters
These Effect the NET permeability of the drug:
Passive Diffusion (lipinski’s rules)
Uptake Transport (w/transporters)
Paracellular (between the cells, tight membranes)
Pinocytosis
Efflux transport (bring drug OUT)
Uptake Transporters
Enhance the absorption of drug molecules in the INTESTINE
Enhance the distribution of drug into some organs.
- Oligopeptide transporters (PEPT1, PEPT2)
- Large NEUTRAL amino acid transporters (LAT1)
- Monocarboxylic Acid Transporter (MCT1)
- Organic anion transporters (OATP1, OAT1, OAT3)
- Organic cation transporters (OCT1)
- Bile acid transporters (NTCP)
- Nucleoside transporters
- Vitamin transporters
- Glucose transporters (GLUT1)
Efflux Transport
Oppose absorption of molecules on luminal surface of GI epithelial cells.
Oppose distribution of drugs from the bloodstream into organs (like brain).
P-glycoprotein (PGP, MDR1)
Breast Cancer Resistance Protein
Oligopeptide Transporters
PEPT1/2
Uptake Transporters
enhance uptake of dipeptides & tripeptides (2&3)
- *but not for INDIVIDUAL amino acids or TETRApeptides*
- ***NOT 1/4*
NH2-C-C=O or NH2-C-COOH (terminal)
Valganciclovir / Valacyclovir = dipeptides
Large Neutral Amino Acid Transporters
LAT1
Uptake transporter on apical membrane of endothelial cells of BBB
Transports Amino Acids w/ LARGE hydrophobic sidechains
(LEU / PHE)
ex. helps Methyldopa/levodopa get across BBB
Monocarboxylic Acid Transport
MCT1
Uptake Transporter on apical membrane of endothelial cells of the BBB & INTESTINE
Uptake of ACIDS
HYDROLYSIS helps w/ absorption of acids
ex. SALICYLIC ACID, STATINS
Organic Anion Transporters
OATs & OATPs
Uptake transporter for ORGANIC ANIONS
>Enhance renal clearance / liver intake / tissue distribution
cause Drug Drug Interactions
examples:
- Beta Lactam Antibiotics
- NSAIDs
- Antivirals
- AZT / Acyclovir
- fexofenadine/enalapril
Case:
Two Drugs are BOTH substrates of OAT Transporter
Overtime, Concentrations of BOTH Drugs DECREASE
Since transporters are the same, MORE OAT is present.
MORE OAT Transporters = MORE Drug is EXCRETED out
Case:
Drug 1 blocks OAT Transport
Drug 2 is a substrate of OAT
Overtime, concentration of DRUG 2 INCREASES
Passive permeation of DRUG 2 is slow because Drug 1 is blocking the OAT transporter.
Enthalpy
ΔH
A thermodynamic quantity equivalent to the total heat content of a system. It is equal to the internal energy of the system plus the product of pressure and volume.
ΔH
ΔG= ΔH - TΔS
Entropy
ΔS
A thermodynamic quantity representing the unavailability of a system’s thermal energy for conversion into mechanical work, often interpreted as the degree of disorder or randomness in the system.
ΔS
ΔG= ΔH - TΔS
Binding Occurs if ΔΔG<strong>binding</strong> is ______?
NEGATIVE!
ΔΔG<strong>binding</strong> = BOUND - Unbound
BOUND: ΔGprotein-ligand/S + ΔGsolvent2
Unbound: ΔGprotein/S + ΔGligand/S + ΔGsolvent1
Kd
Kd≅Ki
*Kd = Equilibrium Binding Constant
Kd = Koff / Kon
Koff = Dissociation rate constant min-1
Kon = Association Rate Constant M-1min-1
*There are multiple ways to arrive to the same Kd. Compounds with the same Kd may have very different values of koff and kon.
Covalent vs Non-Covalent
Drug Receptor INHIBITION
Non-Covalent Inhibition = Bond dissociates over TIME
Covalent Inhibition = Can be Reversible or Irreversible
>leads to INCREASED residence time
Irreversible Covalent Inhibitor
Irreversible = Protein has to be RECYCLED
Inhibitor stays in the binding site until the whole protein is recycled.
ex. β-lactam ring and DD-transpeptidase
Reversible Covalent Inhibitors
Reversible = Covalent bond but the bond will dissociate spontaneously
- ex. Active Cysteine > Attacks Amide group*
- will eventually collapse back and let go of the molecule*
Hydrophobic Effect
TYPICALLY, Hydrophobic Drug would reorganize/disrupt the water molecules resulting in a DECREASE IN ENTROPY (unfavorable)
INSTEAD, hydrophobic drug HIDES (binds) in the binding site of the target and displaces trapped water.
This is entropically favorable b/c the water wants to return to the BULK(the other water molecules) water.
~10 fold improvement in ΔΔGbinding if you remove the water first
pKi & Binding Strength
Kd≅Ki
pKi = (-log10Ki)
10 fold decrease in K<u>i</u> = 1 pKi increase
100nM to> 10nM = 1 pKi increase
LARGER the pKi => STRONGER the drug binds (more potent)
smaller the Ki => stronger the drug binds
A 10 fold decrease in Ki (size, nM/uM)
(= INCREASE of 1 pKi )
is ______ in free energy of binding (ΔG)
ΔG of -1.37 kcal/mol
or
ΔG of -5.73 kJ/mol
- *The LESS of a drug you need (smaller size), the more POTENT it is*
- b/c less of it is needed to inhibit the drug target*
Order of Electronegativity
O > N > C > S
A 1000 fold decrease in Ki (size, nM/uM)
(= INCREASE of 3 pKi )
is ______ in free energy of binding (ΔG)
ΔG of -4.11 kcal/mol
or
ΔG of -17.2 kJ/mol
- *The LESS of a drug you need (smaller size), the more POTENT it is*
- b/c less of it is needed to inhibit the drug target*
Free Energy gained from burying hydrophobic vs POLAR surfaces
hydrophobic = 0.03 kcal/mol/A*2
vs
POLAR = 0.01 kcal/mol/A*2
10 fold (1 order) increase in Potency (10x decrease in Ki)
CAUSED BY
1-2 hydrogen bonds
Every 46A*2 of buried hydrophobic surface (=methyl group)
Residence time
Why affinity is not the whole story
t1/2 = 1 / koff
Compounds with the same Kd may have very different values of koff and kon.
You can have identical/rapid clearance (plasma half-life is short)
and still have one drug with a MUCH LONGER RESIDENCE TIME (koff)
Why is potency of drugs important?
More Potent the drug
=
Less of it is needed to inhibit drug target
Better Therapeutic Index* (TI)
*provided that both drugs have equal LD50
Therapeutic Index (TI)
TI = LD50 / ED50
LD50 = LETHAL dose at which 50% of model animals die
*want to be as HIGH as possible
<span>ED</span>50 = EFFECTIVE dose at which desired effect is observed in 50% of animals
*want to be as LOW as possible
Therapeutic Window
Below TOXIC concentration
Above subtherapeutic concentration
More Potent = Wider Therapeutic Window
DISTANCE BETWEEN GROUPS OF
Electrostatic interactions:
Coulombic charge-charge
Charge-dipole
Charge-induced dipole
Coulombic charge-charge = ~1/r
**More than 3 ANGSTROMS = no h-bond
otherwise salt bridge (link between acid/base)
Long distance, do not require hydrogen bonding between +/-
Charge-dipole = ~ 1/r2
Charge-induced dipole = ~1/r4
DISTANCE BETWEEN GROUPS OF
Nonelectrostatic interactions:
VDW
dipole-dipole
VDW REPULSION = ~ 1/r12
London Dispersion attraction = 1/r6
IDEALLY - 1.7-2.0 ANGSTROMS
depending on the atoms
Dipole-Dipole = 1/r6
DISTANCE BETWEEN GROUPS OF
Short Range Repulsion
HYDROGEN BONDS
Short Range Repulsion = ~ 1/r 12- 1/r10
-steric clash of VDW radii
HYDROGEN BONDS = 1/r3
Bond Distance for HYDROGEN BONDS
IDEALLY ~2.6-3.0 ANGSTROMS
<3 pKBHX( 1/r3 )
- *In heterocycles with N and O, N is by far the strongest HBA.*
- Both N and O can participate in hydrogen bonds when it leads to better binding energy*
Bond Angles for H-BONDS
for N-H —– O
The MORE angle deviates from 180°, the LESS energetically favorable this bond would be.
*typical values are often >150°
for C=O —– H
The angle has a much broader range;
between 100 and 180°
Dielectric Problem
Effect of “Shielding”
Coulombic interractions become WEAKER and decay FASTER
Shielding = Layers of Water In-between
These can make electrostatic interactions weaker or stronger
Optimal Distance for vdW Interactions
(Lennard Jones Potential)
optimal Distance = 1.7 - 2.0 Angstroms
~depending on the atoms
vDW repulsion =1/r12
london dispersion ATTRACTION =1/r6
Mismatch in Drug Receptor Interactions can cause
DRUG RESISTANCE
Drug is unable to bind to the MUTATED receptor
ex. ARG (+) becomes GLU (-)
Results in a STRONG repulsion
Why do drugs have multiple types of interactions with their targets?
Hydrophobic interactions are the driving force for drug-target binding
- Solubility (lipophilic compounds would not dissolve in water)
- Permeation across membranes (lipophilic compounds have trouble permeating membranes)
- Metabolism (lipophilic compounds are often trapped by plasma proteins and metabolized)
- Cooperativity, stabilization of drug-receptor binding that is larger than the sum of energies of individual ligand-receptor interactions
Cooperativity
Multiple interactions acting together is greater than the sum of the individual binding free energies
*think feet in mud example
Koff
Quantitatively:
ΔΔG = Sum of ΔΔG’s
Fsp3 Values
Carbons with 3 other filled orbitals
ie CH3 or CCh2
MORE Fsp3 Molecules = MORE Lipophylic (PERMEABLE)
or less water soluble
