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MedChem Midterm 3 > Lipid Membranes and Drug Targets > Flashcards

Lipid Membranes and Drug Targets Flashcards

1
Q

Hydrophobic Effect

A

Effect of Oil-drop in Water

  • Non-polar molecules stick together in polar media (water)
    • in a way to MAXIMIZE # of POLAR interactions
      • =EXOERGIC
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2
Q

Free Energy Aspects

of Amphiphile Aggregation

A
  • Ordered Water molecules that have fewer interactions with other molecules @ surface of Nonpolar solute
    • –> are squeezed out
  • ​Formation of lipid aggregate (ampiphatic complexes)
    • Favorable both enthapically & Entropically
      • ​VDW
      • Enthalpic - interaction amoung water
      • Entropic - water ordering
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3
Q

Phospholipid Aggregates

Different Forms

A
  • Micelle / Hexoganal Phase
    • ​​individual units are WEDGE-shape
      • head + 1 tail
  • Bilayer
    • ​indiv units are CYLINDRICAL
      • head + 2 tails
  • Liposome
    • ​aqueous cavity
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4
Q

Critical Micelle Concentration

CMC

A
  • Specific CONC at which a monomeric amphiphile begins to form micelles
    • typically 10-10M for membrane phospholipids
  • HIGHER CMC Values caused by:
    • ​Shorter chains
    • Greater negative charge
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5
Q

Phospholipid Structure

A
  • Polar HydroPHILIC head
    • ​Choline - Phosphate - Glycerol =
  • Non-polar hydroPHOBIC tail
    • ​= 2 hydrocarbon tails
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6
Q

Sphingolipid

​*not found in bacteria

A
  • A Polar Membrane Lipid
    • a Glycolipid
    • Have mostly saturated fatty acid chains
      • –> TIGHTER packing in bilayers
    • Presence of HB amide bonds –> more rigid
  • Consist of:
    • Sphingosine + FA + Mono/Oligosaccharide
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7
Q

Glycerophospholipids

A
  • Glycerol
    • ​2 FA’s + (PO + Alcohol)
  • ​Not very rigid compared to sphingolipids
    • more UNSATURATED = kinks
  • BLOOD GROUP ANTIGENS
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8
Q

Galactolipids (Sulfolipids)

A
  • Polar Membrane Lipid - Glycolipid
  • Glycerol
    • ​2 FA + (Mono/disaccharide + SO4)​
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9
Q

Triacylglycerols

A
  • neutral Storage Lipid
  • Glycerol
    • ​3 FA’s
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10
Q

Blood Groups differ by presense & Type of what?

A

Glycosyl Transferase

  • Blood group antigens are GLycosphingolipids
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11
Q

Cholesterol

A
  • Eukaryotic membrains contain Cholesterol
    • ​*not found in bacteria
  • Orientated w/ -OH facing the aqeuos phase
  • Polycyclic Structure
    • –> imparts RIGIDITY to membranes w/ a lot of cholesterol
  • Found most in Plasma Membrane
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12
Q

PhosphatidylCHOLINE (PC)

A
  • ​found only in prokaryotes
    • mainly in Mito
        • Inner Membranes
  • ​​distributed @ the OUTER MONOLAYER
    • ​along with sphingomyelin
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13
Q

Cardiolipin

A
  • Lipid found mostly in MITOCHONDRIA
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14
Q

PhosphatidylEthanolamine (PE)

A
  • PE found in both prokaryotes & eukaryotes
    • mainly in Mitochondria
  • ​Negatively charged phospholipid
    • located @ INNER leaflet of bilayer
      • ​involved in RECRUITMENT of POSitive signaling proteins
        • ​to the membrane surface
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15
Q

Flippase

A
  • Catalyzes TRANSVERSE DIFFUSION
    • ​“FLIP-FLOP” of phospholipid
    • from facing outer membrane to inner membrane
      • very slow –> very fast
  • Lateral diffusion occurs very fast UNCATALYZED
    • ​also rotation along molecular axis is fast
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16
Q

Liquid-Crystalline Phase

(fluid state)

A
  • Biological membranes MUST STAY liquid-crystalline
    • ​TO BE FUNCTIONAL
      • ​​Need to be ABOVE transition temperature
  • ​​if below transition temperature
    • ​–> GEL STATE (non functional)
      • ​aka paracrystalline state
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17
Q

How do bacteria adapt to lower temperatures?

A
  • they use more unsaturated fatty acids
    • like OLEIC ACID (unsaturated = MORE BENT)
  • ​​​Enable bacteria membrant to REMAIN liquid crystalline
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18
Q

Traits of Phospholipids with

More Unsaturated Bonds

A
  • Thinner Bilayers compared to saturated chains
    • Cis-double bonds are shorter
    • ​Shorter & Occupy LARGER SURFACE AREA
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19
Q

Passive transport is fastest for molecules with moderate hydrophobicity. Why?

A

We want the molecule to readily enter the membrane but we also do not want it to leave so quickly

20
Q

Membranes are refractory to polar molecules.

Why?

A

Phosphoplipid membrane has polar heads

polarity will block molecule from entering

21
Q

Topology of membrane proteins can be predicted from hydropathy indices.

What’s that?

A
22
Q

2 Dimentional Liquid

or

Liquid Crystalline State

A
  • Rapid conformational & rotational changes in:
    • ALKANE chains & head group orientation
  • Planar bilayer is maintained
  • NO LATERAL Movement observed within 5Nanoseconds**​​
23
Q

Uncatalyzed lateral Diffusion

A
  • A motion in liquid-crystalline bilayers
    • LATERAL
  • occurs very FAST
    • because the forces VDW are very weak
24
Q

Uncatalyzed Transverse Diffusion

“flip-flop”

A
  • Motion in liquid-crystalline bilayer
  • occurs very SLOW
    • ​during transit, e- charged head group must be stripped of solvating water molecules
  • ​*there is also fast rotation along the molecular axis
25
Q

Glycophorin A

Integral Membrane Protein

A
  • Contains a Single Helical transmembrane segment
    • hydrophobic AA side chains allow the segment to sit between the phospholipid bilayer
  • ​Heavily glycosilated @ extracellular part
    • w/ NEGATIVELY charged sialic acid
      • –> ensure that eruthrocyte do not adhere to walls of blood vessels
26
Q

Membrane Pore / Channel

Integral Protein

A
  • Formed by assemblies of either a-helical / b-sheeted proteins
  • Responsible for:
    • signaling
    • ligand gated channels
    • voltage gated ion channels
    • membrane transporters
27
Q

Bacteriorhodopsin

Integral Protein

A
  • Seven-Pass Membrane receptor
    • important for cell signaling
      • GPCR = great target for drug design
      • regulate processes from sensing to neuronal transmission
  • Proton Pump
    • allow H+ to leave cell
28
Q

Hydropathy Indices

A
  • number representing the hydrophobic or hydrophilic properties of a AA sidechain
    • GLU / ASP = most polar
    • PHE / TRP = most hydrophobic
  • ​Used to PREDICT TRANSMEMRANE DOMAINS
    • ​Bacteriorhodopsin = 7 hydrophobic domains
    • Glycophorin = 1 hydrophobic domain
29
Q

Membrane Permeability:

Hydrophobic Molecules

A
  • Easily cross the membrane
  • O2 / CO2 / N2 / Benzene
30
Q

Membrane Permeability:

Small Uncharged POLAR Molecules

A
  • Membranes are permeable to small noncharged molecules
    • Ex. Water, Urea, Glycerol
      • Must have LOW POLARITY
  • ​​800 Daltons = Upper MW limit to cross cell membrane passively
    • those greater than this need a transporter system
    • low MW is a necessary but insufficient condition of BV
31
Q

Membrane Permeability:

IONS

A
  • CHARGED molecules can NOT cross bilayer
    • especially NEGATIVE
32
Q

Simple Diffusion

A

Non-Polar Compounds Only

Down Concentration Gradient

  • <800 daltons
  • Low MW is necessary but insufficient condition of BV
33
Q

Fascilitated Diffusion

A

Down Electrochemical gradient

uses a transporter

34
Q

Primary Active Transport

A

AGAINST electrochemical gradient

USES ENERGY

35
Q

Secondary Active Transport

SYMPORTER

A

AGAINST electrochemical gradient

Driven by ION moving down the gradient

both molecules move in SAME direction

antiporter = two molecules in opposite directions

36
Q

Ion Channel

A

Down Electrochemical gradient

may be gated by a ligand or ion

37
Q

Ionophore-mediated ion transport

A

Down electrochemical gradient

38
Q

Membrane Bound GLUCOSE transporter

A
  • HydroPHILIC / phobic properties of a-helices
    • polar surface of the channel pore
      • Asn / Ser / Thr
    • interact w/ polar -oh groups of glucose
39
Q

Selective Serotonin Reuptake Inhibitors

SSRI

A
  • Key in antidepressants ~ Paroxetine
    • Block Serotonin transporter w/ Ki =0.34 nm
  • ​​​​​Toggles between outward / inward facing conformations
    • ​​Outward = open extracellularly
    • Inward = open to cytosol
  • ​Symporter
    • hydrogen and ligand go in the SAME direction
40
Q

Drug Transport Predictors

A
  • Factors that help determine Bioavailability
    • ​Octonol / Water Partioning = logP
    • Artifical Membranes
    • Cell Culture Systems - Cell Monolayer
      • ​passive transport
      • Cell assisted transport
        • ​​transcellular / paracellular (inbetween)
        • Carrier mediated transport
        • Transport proteins
41
Q

Lipid Partitioning Vs Membrane Permeation

A

logD = 1-2 is MOST ideal, HIGHEST FLUX

(pH 7.4)

  • flux = mass transfer via artifical membrane %
  • bimodal relationship
    • ​lipophilicity vs mass transfer
  • Very lipoPHILIC drugs can penetrate membrane
    • but CAN NOT LEAVE
  • Very hydroPHILIC drugs cannot get solubized in membrane
42
Q

Lipid Partitioning vs Membrane Permeation

k1 & k2

A
  • k1 = rate constant of transport from:
    • ​Aqueous –> liquid phase
      • ​INCREASES as logD Heightens
  • k2 = REVERSE of K1
    • DECREASES as logD Heightens
43
Q

Passive Vs Carrier-Mediated Transport

A
  • Carrier Mediated Transport = LIMITED by transporter
    • Levels off at Vmax
    • high km = weak binding
      • when concentration = half maximum velocity
  • Overall Transport is a sum of the two components
44
Q

Passive Transport

A
  • Linearly dependent on concentration
    • Non-saturable, unlike carrier mediated transport
  • ​NOT SUBJECT TO INHIBITION
  • Less structure specific than carrier mediated
    • general dependence on LIPOPHILICITY
  • Less cell-type specific than carrier mediated
45
Q

Carrier-Mediated Transport

A
  • Non-Linearly dependent on concentration
    • ​SATURABLE
  • ​SUBJECT TO INHIBITION
  • MORE structure specific
    • dependence on lipophilicity could be identified in narrow chemical series
  • Cell type specific
    • requires expression of transporter
46
Q

Efflux Pumps

A
  • can Work AGAINST the gradient (ATP)
    • ​pump drug out of the cell
      • ​cytosol –> out of cell
  • _Blocking efflux pump is a strateg_y:
    • for maintaining higher drug conc. after administration
47
Q
A

MedChem Midterm 3 (7 decks)

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