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PHRM 100 – IMC > IMC 05: Proteins as Targets for Drug Molecules > Flashcards

IMC 05: Proteins as Targets for Drug Molecules Flashcards

1
Q

Are carbohydrates water soluble?

A

yes

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2
Q

What is the general structure of carbohydrates?

A

Cn H2n On

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3
Q

What are glycoconjugates?

A

glycoproteins or glycolipids that serve as molecular tags important in cell recognition

  • these tags can commonly act as antigens when introduced into a different individual
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4
Q

What are enzymes?

A

proteins that catalyze chemical reactions

  • deep cavities or pockets that make up their ‘active sites’ where chemical transformations take place
  • these pockets can be targeted with drug molecules
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5
Q

What are receptors?

A

proteins that receive and transduce biochemical signals

  • typically, receptors have distinct pockets that can be targeted with drug molecules
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6
Q

What are scaffolding proteins?

A

proteins that provide structural integrity and/or help orient other proteins into complexes

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7
Q

How many important resonance structures do amide bonds have?

A

2

  • normal one
  • negative charge on O + positive charge on N
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8
Q

What are the two general orientations of peptide bonds?

A
  • cis
  • trans
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9
Q

Which peptide bond orientation does steric clash favour?

A

trans amide

  • resonance structures allow for flipping
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10
Q

What restricts the folding patterns of polypeptide chains that make up proteins?

A

combination of:
- double bond character
- amino acid side chains

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11
Q

Peptide/Amide Bond

Double Bond Character of C-N Bond

A

renders amide bonds hydrolytically stable when planar

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12
Q

Peptide/Amide Bond

Electronegativity

A

the more electronegative oxygen atom of the ester is less willing to donate its lone pair to the double bond than the nitrogen atom of the amide

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13
Q

Peptide/Amide Bond

Ester Functional Group Stability vs. Amides

A

ester functional groups are much less stable in aqueous environments than amides

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14
Q

Peptide/Amide Bond

Can amide bonds be cleaved?

A

yes – but generally require an enzyme to catalyze this reaction

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15
Q

Primary Structure of Proteins

A

the order in which individual amino acids that make up a protein are linked together via peptide bonds

  • responsible for distinct folding (2º structure), shape (3º structure), and protein-protein interactions (4º structure)
  • dictates protein folding – changing primary structure can change everything else
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16
Q

Secondary Structure of Proteins

A

local regions of ordered structure adopted by the protein chain (ie. alpha helices, beta sheets)

  • beta strand, beta sheet
  • alpha helix
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17
Q

Secondary Structure

What is a hydrogen bond?

A

non-covalent interaction that occurs between a heteroatom (usually oxygen or nitrogen) and a hydrogen atom attached to another heteroatom

  • subtype of dipole-dipole interactions
  • differences in electronegativity make hydrogen atoms δ+ and heteroatoms δ- (N and C)
  • partially positive (δ+) hydrogen atoms will interact with lone pairs on N and O to make hydrogen bonds
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18
Q

Secondary Structure

Hydrogen Bond Donor (HBD)

A

has a δ+ hydrogen atom – gives away the H atom

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19
Q

Secondary Structure

Hydrogen Bond Acceptor (HBA)

A

is δ- and has a lone pair in a hybrid orbital – accepts the H atom, has a lone pair

  • ie. not involved in aromatic pi system
20
Q

Secondary Structure

Alpha Helices

A
  • held in place by hydrogen bonding between residues in protein backbone – NOT side chains
  • 3.6 residues per helix turn of the helix (residues n, n+4, and n+7 on same side)
  • hydrophobic alpha helices can span membranes
21
Q

Secondary Structure

What amino acids is generally not found in alpha helices? (2)

A
  • proline – proline R group forces an incompatible geometry
  • glycine – due to high flexibility
22
Q

Secondary Structure

Beta Sheets

A
  • anti-parallel beta sheets (common) have good overlap of h-bonding (180º angle)
  • parallel beta sheets (less common) have angled H-bonds (weaker)
  • sequential amino acid R-groups are arranged on opposite sides of the sheet
  • can form additional structures such as beta turns and beta barrels
23
Q

Tertiary Structure of Proteins

A

overall 3D shape
- how the secondary structures and disordered regions are arranged

24
Q

Quaternary Structure of Proteins

A

arrangement of proteins in a multi-protein complex

  • how the tertiary structures are arranged in complexes
  • may be multi-component structures or oligomers of one protein
25
Q

What are common post-translational modifications of proteins?

A
  • phosphorylation of Tyr and Ser by kinases
  • dephosphorylation by phosphatases
26
Q

Chirality

What is chirality?

A

property of chemical compounds that are non-superimposable on their mirror image

  • carbon atom with 4 different substituents will usually be a chiral centre
27
Q

Chirality

What are enantiomers?

A

chiral isomers with one chiral centre

  • have the same chemical and physical properties as each other
  • differ only by how they interact with other chiral compounds and with light
28
Q

Chirality

How do planes of symmetry affect chirality?

A

can make things non-chiral even if they have a carbon atom with 4 different substituents – referred to as meso compounds

29
Q

Chirality

What are diastereomers?

A

isomers that have more than one chiral centre and will have different chemical and physical properties compared to their diastereomers

30
Q

Chirality

A
  • chiral molecules are non-superimposable on their mirror image
  • enantiomers may interact with chiral molecules differently
  • enantiomers interact with light differently
  • carbon atom with 4 different substituents is often a chiral center
31
Q

If a pair of compounds that are chiral isomers (mirror images of each other) have different melting temperatures, what term is best to describe these isomers?

A

diastereomers

32
Q

Ionic Interactions

A
  • especially important in hydrophobic environments (active sites and hydrophobic protein core)
  • on the protein surface, ions interact with water molecules (ion-dipole interactions) which are stabilizing
33
Q

What are the 3 types of van der Waals forces?

A
  • dipole-dipole
  • ion-induced dipole
  • dipole-induced dipole
  • London dispersion force
34
Q

Dipole-Dipole

A

involves interactions between δ+ and δ-

ie. hydrogen bonding

35
Q

Ion-induced Dipole or Dipole-induced Dipole

A

ions or partial charges will induce dipoles by attracting or repelling electrons in the electron cloud

36
Q

London Dispersion Forces

A

(weakest) temporary dipole-induced dipole

  • because electron density is probabilistic, partial charges may result from random electron movement which can also induce dipoles
37
Q

Hydrophobic Interactions

A

describes favourable interactions between two hydrophobic groups in an aqueous environment

  • interaction of hydrophobic groups reduces hydrophobic surface area and reduces the area of highly ordered water matrix
  • major driving force for protein folding and for drug binding to protein active sites
38
Q

π -π stacking (pi-stacking)

A
  • delocalized pi system increases electron density above and below the aromatic ring
  • carbon atoms in the ring are therefore δ+
  • weaker than van der waals forces – small role in protein folding
  • control substrate and drug binding properties
39
Q

cation- π interaction

A

cations (+) can interact with the delocalized electron (-) cloud a benzene ring

40
Q

What is protein folding governed by?

A

Gibbs free energy: ΔG = ΔH - T ΔS

  • ΔG: change in the free energy – if ΔG < 0 then process is spontaneous (ie. protein folding)
  • ΔH: change in enthalpy – energy stored in covalent (disulfide bridges) and non-covalent bonds
  • ΔS: change in entropy – term for the relative disorder (disorder = favoured)
  • T: temperature
41
Q

What is the dielectric constant (D)?

A

measure of the polarity of a solvent or molecular environment

42
Q

Hydrogen bonds are a strong form of _________________.

A

dipole-dipole interactions

43
Q

Ionic interactions are _________ in hydrophobic environments.

A

stronger
(even stronger than hydrogen bonds)

44
Q

Entropy of Protein Folding

What are the 2 conflicting levels of disorder?

A
  • primary structure goes from disordered to highly ordered (decrease ΔS → increase ΔG)
  • H2O network that solubilizes the protein sequence
45
Q

Entropy of Protein Folding

What is the hydrophobic collapse?

A

describes a hydrophobic core forming and excluding H2O molecules

  • entropically driven
46
Q

Entropy of Protein Folding

Hydrophobic interactions in the protein core _______________.

A

exclude highly ordered H2O molecules (increases ΔS → decreases ΔG)

  • hydrophobic residues get inside to the centre by entropy

PHRM 100 – IMC (11 decks)

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