1
Q
Why do only very few drugs contain furan?
A
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
2
Q
Lipinski’s Rules
A
- 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.
3
Q
DESIRED TPSA to be able to cross CELL MEMBRANE
A
TPSA < 140 Angstroms
LESS THAN 140
4
Q
DESIRED TPSA to be able to cross BBB
A
TPSA < 90 Angstroms
LESS THAN 90
5
Q
Huckel’s Rule
A
4n + 2pi
= 2,6,10,14,18 pi electrons
to be AROMATIC
6
Q
Heteroatoms in order of Polarity
A
N is most POLAR
N > O > S
7
Q
Heteroatoms in order of Lipophilicity
A
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
8
Q
pKa trend for basic aromatic heterocycles
A
More Nitrogens = Less Basic ( lower pKa )
9
Q
logP
A
logP = octanol / H2O
Drugs & Bioactive molecules - logP= 1-5
logP=5 >>> 105 parts octanol : 1 part H2O
10
Q
Saturated 5-mem heterocycles
Structural Properties
A
Puckered Conformation
NOT FLAT
ex. pyrrolidine
11
Q
5-membered AROMATIC heterocycles
Structural properties
A
ALL FLAT
ex. Pyrrole (pka 1-5, weak base)
O/S hetrocycles not considered Acid or base
12
Q
Unsaturated 5-membered heterocycles
Structural Properties
A
ALL FLAT
13
Q
Beta-Lactams MOA
A
- β-Lactam antibiotics inhibit DD-transpeptidase
- β-Lactam Covalently Bonds to the ester on DDTP
- Irreversible reaction
14
Q
Factors Affecting Beta Lactam REACTIVITY
A
- 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
15
Q
Effect of Reactivity of Beta Lactam Antibiotics
A
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
16
Q
3-mem heterocycle DRUGS
A
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
17
Q
4-mem heterocycle DRUGS
A
O-containing 4rings = Not all Reactive
Oxetane = NOT REACTIVE
Lactone = REACTIVE
S-containing 4rings = No FDA approved drugs
18
Q
3/4-membered heterocycles
Structural Properties
A
- 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
19
Q
3/4-membered heterocycles
effect on DRUG PROPERTIES
A
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
20
Q
Electronic Properties of 6mem Heterocycles
A
- 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
21
Q
Factors that help diffusion through a cell membrane
A
To INCREASE diffusion / slipperiness (k):
HIGHER = logP or logD
HIGHER = HSA
less = H-bond acceptors & donors
lower = MW
lower = SASA / TPSA
22
Q
SASA
A
SASA = surface area of a molecule accessible to a solvent (WATER)
INVERSELY RELATED TO PERMEABILITY
Decreasing SASA > MORE PERMEABLE (less water solubility)
23
Q
The Higher the density of the packing (pi-pi stacking / sp2 vdw interactions)
A
MORE energy required to disrupt interactions between molecules to achieve dissolution & solubility
MORE difficult for other molecules to get IN BETWEEN
24
Q
TPSA (Topological polar surface area)
A
TPSA = surface area of all the polar parts of a molecule (mainly N,O)
INVERSELY RELATED TO PERMEABILITY
DECREASING TPSA > INCREASES SOLUBILITY
25
HSA
**HSA** = surface area of all the **HYDROPHOBIC** parts of the molecule (mostly all **EXCEPT N/O**)
**INCREASING** HSA \> **INCREASES PERMEABILITY**
26
pH effect on H-bond donor/acceptors
pH dependent!
blue = donor
red = acceptor
27
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
28
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
29
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
30
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
31
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
32
**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_
33
**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
34
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: Δ**G**protein/S + Δ**G**ligand/S + Δ**G**1solvent1
Bound: Δ**G**protein-ligand/S Δ**G**1solvent2
35
**Veber's Rules**
**\>10 rotatable bonds** = **POOR BIOAVAILABILITY**
of Rotatable bond =
#of NON-TERMINAL single bonds
**+**
#single bonds in SATURATED\* ring **-(minus) 4**
* \*saturated ring must have 4 or more carbons*
* \*if connected to an aromatic system, do not count the "touching" single bound*
36
Relationship Between
## Footnote
**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
37
Relationship Between
## Footnote
**Rate of Diffusion & Molecular Weight**
**Larger MW =** _Slower_ Rate of Diffusion
slower to cross the membrane
RACE AGAINST TIME
38
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
39
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
40
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)*
41
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)
42
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
43
Oligopeptide Transporters
## Footnote
**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
44
Large Neutral Amino Acid Transporters
## Footnote
**LAT1**
**Uptake transporter** on **apical membrane** of endothelial cells of **BBB**
Transports **Amino Acid**s **w/ LARGE hydrophobic** sidechains
**(LEU / PHE)**
ex. helps Methyldopa/levodopa get across BBB
45
Monocarboxylic Acid Transport
## Footnote
**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
46
Organic Anion Transporters
## Footnote
**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
47
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**
48
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.
49
**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
50
**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 - T**ΔS**
51
Binding Occurs if **ΔΔG**binding is \_\_\_\_\_\_?
**NEGATIVE!**
**ΔΔG**binding = **BOUND - *Unbound***
**BOUND:** ΔGprotein-ligand/S + ΔGsolvent2
***Unbound:** ΔGprotein/S + ΔGligand/S + ΔGsolvent1*
52
**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.*
53
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
54
**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*
55
**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*
56
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*
57
**pKi **& **Binding Strength**
**Kd≅Ki**
**pKi = (-log10Ki)**
_10 fold decrease in K_i = **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*
58
_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*
59
Order of Electronegativity
O \> N \> C \> S
60
_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*
61
Free Energy gained from burying **hydrophobic** vs _POLAR_ surfaces
**hydrophobic = 0.03 kcal/mol/A\*2**
vs
_POLAR = 0.01 kcal/mol/A\*2_
62
**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)
63
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)**
64
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*
65
Therapeutic Index (**TI**)
**TI** = **LD50** **/ ED50**
**LD50 = LETHAL** dose at which 50% of model animals **die**
*\*want to be as HIGH as possible*
**ED50 = EFFECTIVE** dose at which **desired effect** is observed in 50% of animals
\**want to be as LOW as possible*
66
Therapeutic Window
**Below TOXIC** concentration
_Above subtherapeutic_ concentration
**More Potent = Wider Therapeutic Window**
67
**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**
68
**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**
69
**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**
70
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*
71
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°**
72
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**
73
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**
74
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_
75
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
76
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**
77
Fsp3 Values
Carbons with 3 other filled orbitals
ie CH3 or CCh2
**MORE Fsp3 Molecules = MORE Lipophylic (PERMEABLE)**
or _less water soluble_
MedChem Midterm 2
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