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MSF2 - enzyme kietics > Enzyme kinetic 4 > Flashcards

Enzyme kinetic 4 Flashcards

1
Q

What is the aim of molecular docking?

A

To give a prediction of the ligand-receptor complex structure using computational methods.

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2
Q

What are the disadvantages of High throughput screening?

A
  • Expensive
  • Produces false positive
  • Takes along time
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3
Q

Name an example of a protein docking programme?

A

EADocking

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4
Q

Give example of the 1D descriptors required to identify a good inhibitor?

A
  • MWt
  • chemical composition
  • hydrophobicity
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5
Q

Give example of the 2D descriptors required to identify a good inhibitor?

A
  • Bond order

- degree of branching, flexibility

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6
Q

Give example of the 3D descriptors required to identify a good inhibitor?

A
  • overall charge

- Pharmacore

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7
Q

What is pharmacore?

A

The spatial arrangement of chemical groups that determine its activity

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8
Q

What is Structure Activity Relationships (SAR)?

A

The relationship between the chemical or 3D structure of a molecule and its biology activity.

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9
Q

Why do you need to check the biological activity of each compound?

A

In many cases you do not want long lasting effects, need to know Kon and Koff

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10
Q

What might you do to investigate SAR?

A
  • crystallography
  • screening inhibitor and homologues
  • modify functional groups, if activity is lowered then the group is important and visa versa
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11
Q

What are Lipinski’s rule of five a rule of thumb for?

A

Whether a molecule could be a successful at being a drug?

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12
Q

How many Lipinski’s rules of 5’s are there?

A

4, lololol

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13
Q

What are the Lipinski rules of 5?

A

1)

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14
Q

How do you calculate LogP?

A

P = [D]lipid/[D]water

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15
Q

Why are Lipinski’s rule of five names thusly?

A

All the numbers in the rules are multiple of five

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16
Q

There are no exceptions to the rule of 5. True or False?

A

False, there many examples

17
Q

In silico screening is used to identify potential lead compounds from a database. What does this database assign to these compounds? What is it used for?

A

Scores, rankings and sets of chemical structures.
It is used to pose a prediction.
It is also able to take into account the type of compound you want i.e. hydrophobic. This requires a high resolution structure because you need to exact positions of the side chains to know the chemical state of the binding site.

18
Q

What are the three general methods of in silico docking?

A
  • Dock compound to active site
  • Define active site of protein - build component to fit in active site
  • Define binding site to software and also a small part (fragments of substrate)
19
Q

What is rigid docking?

A

Docking in which ligand is treated as a rigid structure and only translational and rotational degrees of freedom are considered.

20
Q

The ligand is presented as sphere centre in rigid or flexible docking?

A

rigid docking

21
Q

What is the advantage of rigid docking over flexible docking?

A

It enables you to search 100-1000s of compounds without much laborious work

22
Q

What is flexible docking?

A

Docking in which the substrate is assumed to have some flexibility along torsion angles which allows for side chain rotation but doesn’t allow for big conformational changes.

23
Q

What is the advantage of flexible docking over rigid docking?

A

It provides a higher hit rate in terms of identifying possible conformations.

24
Q

Aside from the process being time consuming what is an issue with flexible docking?

A

If the protein undergoes large conformational change then the system won’t be able to produce good hits.
ie open and closed states.

25
Q

What are some things to consider before docking?

A
  • Need high resolution structure
  • At 2A you can’t see hydrogens, just is a large limiting factor because all programmes require hydrogen to be present
  • Don’t know if acid is protonated (look at pH and pKa)
  • If ring is it chair or boat
26
Q

What is Structure based fragment screening?

A

Where you have a known active site and build up ligands by fragments.

27
Q

What is lead identification by fragment evolution?

A

An initial fragment is optimized by by adding functionality to bind to adjacent regions of the active site

28
Q

What is lead identification by fragment linking?

A

Two (or more) fragments, which bind to proximal parts of the active site, are joined together to give larger, higher affinity-binding molecule

29
Q

What is lead identification by fragment self-assembly?

A

Fragments with complementary functional groups are allowed to react together in the presence of the protein target and the most potent larger molecule is detected. This includes approaches usually termed dynamic combinatorial chemistry

30
Q

What is lead progression by fragment optimisation?

A

Fragment approaches are used to optimize drug-like properties of a lead other than just binding affinity

31
Q

What does thymidylate synthase do?

A

Maintain the dTMP pool and therefore is critical for DNA replication and repair.
Thus area of interest in cancer research

32
Q

What is the difference between potency and efficiency?

A

potency - the mount of substance required for a desired effect
efficiency - the maximum strength of the drug itself, at saturating drug concentrations

33
Q

What is pharmokinetics?

A

Determining the fate of xenobiotics

34
Q

What is pharmodynamics?

A

determining the biochemical and physiological effects of drugs, the mechanism of drug action, and the relationship between drug concentration and effect

35
Q

What criteria must drug leads fulfil?

A

1) Pharmacodynamic properties
2) Physiochemical properties – lipidphilic – will it be able to pass the membrane.
3) Pharmacokinetic properties - how long will it remain in body
4) Chemical optimisation – how easy is it to make chemical modifications.
5) Patentability

MSF2 - enzyme kietics (5 decks)

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