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MedChem Midterm 3 > Proteins as Drug Targets > Flashcards

Proteins as Drug Targets Flashcards

1
Q

Amino Acids & Proteins

A

Only L-Amino Acids are Present in proteins

  • 1* Structure
    • sequence of AA’s joined by peptide bond
  • 2* Structure
    • folding into alpha helices / beta sheets
  • Functions:
    • Structural / Mechanical (keratin/collagen)
    • Coordinated motion
      • ability to contract (actin)
    • Catalysis of chemical rxns
    • Transport / Storage (hemoglobin)
    • Immune protection (AB’s)
    • Signals (hormones/peptides/insulin)
    • transmembrane receptors
    • Control of gene expression
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2
Q

NonPolar Aliphatic R-Groups

A

plus Cysteine (-SH) for some ppl

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3
Q

Polar, Uncharged Groups

A
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4
Q

Aromatic R Groups

A
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5
Q

POSITIVEly charged R Groups

A
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6
Q

NEGATIVELY charged R groups

A
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7
Q

Flexibility of Peptide Chain

A

Only rotations about the N-Ca (phi) and Ca-C1 (psi) bonds are allowed.​

shown by Ramachandran Plot

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8
Q

Alpha Helix Structure

A
  • Integrity maintained by the H-Bonds between n & n-4 residues
  • More stable in hydroPHOBIC environments
    • but in general LESS stable than beta sheets
  • RIGHT HANDED
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9
Q

Beta Sheet Structure

A

Can be Antiparallel or Parallel

  • ANTIparallel beta sheets are more preferred (more HB’s)
    • ​connected by B-turns
      • = frequent motifs recognized by other proteins
      • Drugs try to MIMIC beta turns
        • IkBa transcription regulator
    • GLY / PRO residues found on beta turns
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10
Q

Why proteins w/ a large # of CYS are more rigid?

A
  • Cysteines -SH can crosslink to form DISULFIDE BONDS
    • ​–> more crosslinking –> more rigid
    • –> Covalent bond that are stable at high temps
    • Can still be destablized
      *
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11
Q

Which Bond in Peptides is Shorter?

Ca-N or C1-NH

A

C1-NH bond (peptide)

has partial double bond character

overlap of 2p nonbonding orbital with nitrogen group

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12
Q

Ramachandran Plot

A
  • Contour Plot showing potential enrgies of peptide fragments
    • as a fxn of the angle of rotation about 2 flexible bonds
    • Ca-N & Ca-C
  • Shows that combinations of these angles are more FAVORABLE than others
    • Ex. Antiparallel B-sheets > parallel beta sheets
      • RIGHT handed alpha helix > left handed
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13
Q

Reversible Enzyme Inhibitor

A

Inibition of enzyme activity that is REVERSIBLE

typically NON-covalent

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14
Q

Irreversible Enzyme Inhibitor

A

Inhibits enzyme for an EXTENDED period of time

typically, but NOT always, covalent

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15
Q

Enzyme INACTIVATOR

A

IRREVERSIBLE inhibitor

  • Typically associated w/ Covalent / irreversible modification of an enzyme active site
  • Acetylation of Ser530 of COX-2 by ASPIRIN
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16
Q

Enzyme INHIBITOR

A

Slows or Blocks enzyme catalysis

  • Associated with reversible alteration of enzyme catalysis
  • Ex. Blockade of the active site by SALICYLIC ACID residue in COX-2
    • from Aspirin
    • aspirin does BOTH, inactivates and inhibits
17
Q

Why are Enzymes the most promising Protein Targets

for drug design?

A
  • Enzymes are PURIFIED more easily than receptor proteins
  • CRYSTALLIZED 3d structures are easier to establish
  • Enzyme inhibitors may look like substrates
  • Only can use enzyme mechanism for inhibitor design
18
Q

Ideal Enzyme target

A
  • for foreign organism or abberant cell:
    • ​–> enzyme that is ESSENTIAL FOR GROWTH
      • ​but not needed in humans
  • ​​Ideally want a target that only has 1 ligand
    • But this is very rare
    • most drugs are promiscuous
19
Q

Catalytic Efficiency of enzymes result from…

A

Very tight binding of the TRANSITION STATE

20
Q

Orthosteric

A

Non-Allosteric Interactions

  • Enzyme may have multiple binding sites
    • There can be more than one substrate
21
Q

Allosteric Interaction

A
  • Enzyme NEEDS the allosteric ligand to be bound @ the allo site
    • –> so that the actual substrate can bind
  • Binding modulates the structure of the substrate binding site
22
Q

Binding to Catalytic Site

A
  • Free energy of the complex (bound enzyme) should be LOWER than the SUM of each component
    • Low Complex Energy = Tighter Binding***
  • ​***Needs only to be low enough to provide significant enzyme occupupency at phys. ligand conc.
23
Q

Enzymes are NOT optimized for the tightest binding of substrates….

A

INHIBITORS ARE

24
Q

Why does it not make sense for an enzyme to bind the ligand much more tightly than [L]?

A

When L = 0.1 –> 11% of the protein is bound

When L = 10Kd –> protein is already 91%

There is already complete binding at 10kd, not much different from going to 100kd or 1000kd

25
Q

KD

A

SMALLER the KD = Greater Binding Affinity

equilibrium dissociation constant, measures binding affinity

26
Q

Activation energy barrier for catalyzed reaction is

much SMALLER than the non-catalyzed

A
  • This diffrence is from the very TIGHT binding of the transition state
    • NO POTENTIAL ENERGY MINIMUM
      • –> no finite life time
  • For drug design:
    • We simply try to MIMIC transition states
27
Q

Transition State Mimics

can reproduce TS’s…

A
  • Geometry
    • ​sp3/sp2
  • Electronic state
    • ​presence of -/+ charges resulting from partial bond breaking
  • Longer Seperation
    • ​between interactions
  • Specific Conformation
    • ​substrate adopts the reaction trajectory
  • TSAI’s require knowledge of enzyme mechanism
28
Q

TSAI’s as drugs:

Biochemical Mech. of HMG CoA Reductase

A
  • HMG CoAR = NADH dependent reductase
    • Converts HMG-CoA –> Mevalonate
  • Step 1/1:
    • Reduction of HMG w/ NADPH via TETRAHEDRAL INTERMEDIATE (TI)
      • ​first aldehyde then alcohol
    • Transition state of 1st rxn is “late”
      • reproduces ost of the feature of the TI
  • Stereoselective
  • Interaction of -OH with the LYS side chain is KEY
29
Q

HMG-CoA Reductase Inhibitors

A
  • Statins - discovered as a TSAI of HMG-CoA
  • Typically, (Enzyme-substrate-cofactor complex)
    • LYS make HB bond to C=O group of HMG
  • With statin (enzyme-inhibitor complex)
    • ​-OH of inhibitor makes a STRONGER HB to NH3 of lysine
      • –> 104 INCREASE in POTENCY
30
Q

Induced Fit

mechanism that Ensures substrate specificity

A
  • Complex ligand binding process that involves:
    • Changes in the structure of the Protein and/or Ligand
  • ​​​Ligand –> Protein conformation change
    • Provide best alignment with interacting residues
  • Ligand –> Binds to a form of the protein that @ conformational EQ
  • Ex. in hexokinase rxn:
    • ​Enzyme is NOT active until it’s bound with both ATP & Glucose
      • If it were HK would xfer P–>H2O INSTEAD of glucose
31
Q

Themotoga Maritima

Maltotriose

A
  • Maltotriose –> (Gram negative bacteria ) enzyme
    • –> Inhibits the bacteria of a necesary nutrient
    • = strategy of development of Antibacterias
  • ​Conformational change occurs
32
Q

Conformational Change in

Tyrosine Kinases

A
  • TK’s become enzymatically ACTIVE
    • after ligand binding
  • –> Autophosphoralation on TYROSINE residue
    • –> Conformational change of FGFR1 Kinase Domain
      • –> ACTIVE conformation
  • Both active / inactive conformations are targets of drug design
    • 20 TK inhibitors are in clinical use
33
Q

Both Enzyme & Substrate conformations

are altered upon complex formation

A

Both conformations are altered

  • Ligand
    • –> adopts conformation that is FURTHER along the rxn coordinate
    • better positioned to enter the TRANSITION State
      • ​–> MINIMIZE the activation energy barrier
  • Ex. bacterial enzyme’s biosyntheisis of histadine
34
Q

IC50

inhibition constant

A
  • Concentration of INHIBITOR that reduces activity of a protein to
    • HALF MAXIMAL VALUE
    • depends on the measurement conditions
  • For Kinase Inhibition
    • @ the IC50 = rate of kinase is 50%
  • NOT A PHYSICAL CONSTANT
35
Q

Ki

inhibition constant

A

Dissociation constant of Kinase Inhibitor Complex

characterizes the AFFINITY of ATP along w/ KD

  • Measuured by monitoring rates of kinase rxn in the presence of a present concentration of INHIBITOR
      • varying concentrations of ATP
  • PHYSICAL CONSTANT
36
Q

Competitive Inhibitor

A
  • Drug that displaces ATP from its binding site
    • synonomous to ANTAGONIST for RECEPTORS
37
Q

Cheng-Prusoff Equation

A

Shows the relationship between IC50 & Ki

  • IC50 = Ki when [L] = 0
    • does not occur experimentally
      • b/c rate of enzymatic rxn can not be ZERO
  • IC50 > Ki
    • ​when ligand concentrations [L] are > 0
  • you can not use IC50 for DIFF drugs as a measure of their potency
    • ​UNLESS measurements were carried out w/ the same [L]
38
Q

MDR P1

Multiple Drug Resistance Protein 1

A
  • AN EFFLUX PUMP / USES ATP
    • PUMP DRUG OUT OF THE CELL
  • Realtively structure non-selective
    • ​AS LONG AS MOLECULE IS HYDROPHOBIC
    • ​​Removes both drugs and non-therapeutic hydrophobic molecules

MedChem Midterm 3 (7 decks)

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