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MedChem Midterm 2 > Random Questions > Flashcards

Random Questions Flashcards

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

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2
Q

Lipinski’s Rules

A
  1. MW > 500
  2. logP >5
  3. > 5 H-bond donors (expressed as the sum of OH and NH groups)
  4. > 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)
  5. 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.

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3
Q

DESIRED TPSA to be able to cross CELL MEMBRANE

A

TPSA < 140 Angstroms

LESS THAN 140

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4
Q

DESIRED TPSA to be able to cross BBB

A

TPSA < 90 Angstroms

LESS THAN 90

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5
Q

Huckel’s Rule

A

4n + 2pi

= 2,6,10,14,18 pi electrons

to be AROMATIC

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6
Q

Heteroatoms in order of Polarity

A

N is most POLAR

N > O > S

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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

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8
Q

pKa trend for basic aromatic heterocycles

A

More Nitrogens = Less Basic ( lower pKa )

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9
Q

logP

A

logP = octanol / H2​O

Drugs & Bioactive molecules - logP= 1-5

logP=5 >>> 105 parts octanol : 1 part H2O

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10
Q

Saturated 5-mem heterocycles

Structural Properties

A

Puckered Conformation

NOT FLAT

ex. pyrrolidine

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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

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12
Q

Unsaturated 5-membered heterocycles

Structural Properties

A

ALL FLAT

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13
Q

Beta-Lactams MOA

A
  • β-Lactam antibiotics inhibit DD-transpeptidase
  • β-Lactam Covalently Bonds to the ester on DDTP
  • Irreversible reaction
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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
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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

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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

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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

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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
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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

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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
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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

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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)

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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

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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

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25
Q

HSA

A

HSA = surface area of all the HYDROPHOBIC parts of the molecule (mostly all EXCEPT N/O)

INCREASING HSA > INCREASES PERMEABILITY

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26
Q

pH effect on H-bond donor/acceptors

A

pH dependent!

blue = donor

red = acceptor

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27
Q

H-Bond DONORS

A

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

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28
Q

H-Bond ACCEPTORS

A

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

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29
Q

6-membered Heterocycles

Effect on Drug Properties

A

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

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30
Q

Evaluating changes in logP along with TPSA

A

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

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31
Q

Order of Presidence

A

S>O>N

Higher the molecular weight > Higher presidence

*same with naming the molecule

ie. 1,4-thiazepine not 1,4-azethiazepine

32
Q

Saturated 7-Membered Heterocycles in Drugs

A

Several Drugs with N/O 7mem heterocycles ie.

tolazamide, azelastine,emadastine,suvorexant

**There are NO DRUGS w/ Sulfur-containing heterocycles

33
Q

UNSATURATED 7-membered heterocycles

A

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
Q

Solvation and De-Solvation on Drug Receptor Binding

A

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

35
Q

Veber’s Rules

A

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*
36
Q

Relationship Between

Rotatable Bonds & Entropy

A

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
Q

Relationship Between

Rate of Diffusion & Molecular Weight

A

Larger MW = Slower Rate of Diffusion

slower to cross the membrane

RACE AGAINST TIME

38
Q

Privileged Scaffold Types

A

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
Q

Why are Priveledged Scaffolds a EXCEPTION to the lipinski’s rules?

A

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
Q

Types of Uptake & Efflux Transporters

A

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
Q

Uptake Transporters

A

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
Q

Efflux Transport

A

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
Q

Oligopeptide Transporters

PEPT1/2

A

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
Q

Large Neutral Amino Acid Transporters

LAT1

A

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

45
Q

Monocarboxylic Acid Transport

MCT1

A

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
Q

Organic Anion Transporters

OATs & OATPs

A

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
Q

Case:

Two Drugs are BOTH substrates of OAT Transporter

A

Overtime, Concentrations of BOTH Drugs DECREASE

Since transporters are the same, MORE OAT is present.

MORE OAT Transporters = MORE Drug is EXCRETED out

48
Q

Case:

Drug 1 blocks OAT Transport

Drug 2 is a substrate of OAT

A

Overtime, concentration of DRUG 2 INCREASES

Passive permeation of DRUG 2 is slow because Drug 1 is blocking the OAT transporter.

49
Q

Enthalpy

ΔH

A

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
Q

Entropy

ΔS

A

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

51
Q

Binding Occurs if ΔΔG<strong>binding</strong> is ______?

A

NEGATIVE!

ΔΔG<strong>binding</strong> = BOUND - Unbound

BOUND: ΔGprotein-ligand/S + ΔGsolvent2

Unbound: ΔGprotein/S + ΔGligand/S + ΔGsolvent1

52
Q

Kd

Kd≅Ki

A

*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
Q

Covalent vs Non-Covalent

Drug Receptor INHIBITION

A

Non-Covalent Inhibition = Bond dissociates over TIME

Covalent Inhibition = Can be Reversible or Irreversible

>leads to INCREASED residence time

54
Q

Irreversible Covalent Inhibitor

A

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
Q

Reversible Covalent Inhibitors

A

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
Q

Hydrophobic Effect

A

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
Q

pKi & Binding Strength

Kd≅Ki

A

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

58
Q

A 10 fold decrease in Ki (size, nM/uM)

(= INCREASE of 1 pKi )

is ______ in free energy of binding (ΔG)

A

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
Q

Order of Electronegativity

A

O > N > C > S

60
Q

A 1000 fold decrease in Ki (size, nM/uM)

(= INCREASE of 3 pKi )

is ______ in free energy of binding (ΔG)

A

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
Q

Free Energy gained from burying hydrophobic vs POLAR surfaces

A

hydrophobic = 0.03 kcal/mol/A*2

vs

POLAR = 0.01 kcal/mol/A*2

62
Q

10 fold (1 order) increase in Potency (10x decrease in Ki)

CAUSED BY

A

1-2 hydrogen bonds

Every 46A*2 of buried hydrophobic surface (=methyl group)

63
Q

Residence time

A

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
Q

Why is potency of drugs important?

A

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
Q

Therapeutic Index (TI)

A

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

66
Q

Therapeutic Window

A

Below TOXIC​ concentration

Above subtherapeutic concentration

More Potent = Wider Therapeutic Window

67
Q

DISTANCE BETWEEN GROUPS OF

Electrostatic interactions:

Coulombic charge-charge

Charge-dipole

Charge-induced dipole

A

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
Q

DISTANCE BETWEEN GROUPS OF

Nonelectrostatic interactions:

VDW

dipole-dipole

A

VDW REPULSION = ~ 1/r12

London Dispersion attraction = 1/r6

IDEALLY - 1.7-2.0 ANGSTROMS

depending on the atoms

Dipole-Dipole = 1/r6

69
Q

DISTANCE BETWEEN GROUPS OF

Short Range Repulsion

HYDROGEN BONDS

A

Short Range Repulsion = ~ 1/r 12- 1/r10

-steric clash of VDW radii

HYDROGEN BONDS = 1/r3

70
Q

Bond Distance for HYDROGEN BONDS

A

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
Q

Bond Angles for H-BONDS

A

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
Q

Dielectric Problem

Effect of “Shielding”

A

Coulombic interractions become WEAKER and decay FASTER

Shielding = Layers of Water In-between

These can make electrostatic interactions weaker or stronger

73
Q

Optimal Distance for vdW Interactions

(Lennard Jones Potential)

A

optimal Distance = 1.7 - 2.0 Angstroms

~depending on the atoms

vDW repulsion =1/r12

london dispersion ATTRACTION =1/r6

74
Q

Mismatch in Drug Receptor Interactions can cause

A

DRUG RESISTANCE

Drug is unable to bind to the MUTATED receptor

ex. ARG (+) becomes GLU (-)

Results in a STRONG repulsion

75
Q

Why do drugs have multiple types of interactions with their targets?

A

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
Q

Cooperativity

A

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
Q

Fsp3 Values

A

Carbons with 3 other filled orbitals

ie CH3 or CCh2

MORE Fsp3 Molecules = MORE Lipophylic (PERMEABLE)

or less water soluble

MedChem Midterm 2 (6 decks)

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