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Contemporary Themes > Principles Of Med Chem > Flashcards

Principles Of Med Chem Flashcards

1
Q

What is an alkaloid

A
  • a basic N-containing natural product that excludes proteogenic amino acids and DNA/RNA bases
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2
Q

What is a drug

A
  • a compound that interacts with a biological system to induce a biological response
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3
Q

Define the term therapeutic ratio

A

The ratio of maximally tolerated dose to the minimally curative or effective dose

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4
Q

What is the therapeutic ratio defined as for animal models

A
  • it compares the dosage that results in lethal effects in 50% of the cases with the maximally therapeutic dose in 50% of the cases
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5
Q

Define the therapeutic ratio in human patients

A
  • compares the dosage required for toxic effects in 50% of the cases with the maximally therapeutic effect in 50% of the cases
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6
Q

What is an organelle

A
  • a membrane bound compartments or structures in a cell
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7
Q

What are some of the interactions associated with the binding of a drug to its target

A
  • covalent bond
  • ionic bonds
  • hydrogen bonds
  • van der Waals interactions
  • dipole-dipole interactions
  • hydrophobic interactions
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8
Q

Describe the ionic interactions that result when a drug binds to its target

A
  • refers to an attractive binding interaction between groups of opposite charge on the drug target
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9
Q

Describe the H-bonding interactions that result when a drug binds to its target

A
  • most often occur between an electron-rich heteroatom or H-bond acceptor and an electron deficient H-atom the H-bond donor
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10
Q

Describe the van der Waals interactions that result when a drug binds to its target

A
  • very weak interactions that arise between hydrophobic areas of molecules
  • transient areas of high and low electron density in one molecule can induce a dipole in a nearby molecule leading to an attractive interaction that falls off rapidly with distance.
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11
Q

Describe the dipole-dipole interactions that result when a drug binds to its target

A
  • a permanent dipole usually results from the presence of functional groups
  • a drug’s binding site may also posses a permanent dipole
  • if the two dipoles are parallel but opposed there is a beneficial binding effect results
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12
Q

Describe the hydrophobic interactions that result when a drug binds to its target

A
  • to react its target drug must pass through aqueous media therefore drug and target will be solvated
  • solvating water molecules must be stripped away for favourable interactions- costs energy
  • energy loss>energy binding the drug is ineffective
  • hydrophobic regions of the drug and the binding site cannot be solvated here water forms highly ordered layer next to the surface
  • upon binding the water molecules are set free resulting in an entropy increase and the fire a beneficial gain in binding energy
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13
Q

What are the key requirements for an orally administer drug to be effective

A
  • must survive exposure to stomach acids and digestive enzymes
  • must be absorbed from the gut into the blood supply
  • must survive passage through the liver which as large number of metabolic enzymes
  • must be effectively distributed around the body without being competitively absorbed by fat tissue
  • has to have a reasonable lifetime inside the body and not be rapidly excreted
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14
Q

What is Lipinski’s rule of 5 for good oral bioavailability of a drug candidate

A

1) drug molecular weight

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15
Q

Describe the process of lead discovery

A
  • a drug target for a give the disease state is selected
  • a bioassay is developed
  • results in discovery of a lead compound with the desired effect on the drug target
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16
Q

In lead discovery what are the conditions associated with developing a bioassay

A
  • should be simple
  • rapid
  • carried out in intact cells in vitro
17
Q

What are the steps involved in drug design following lead discovery

A
  • design and carry out experiments to determine structure-activity-relationships
  • optimisation of interactions with drug target
  • optimisation of pharmacokinetic behaviour
18
Q

What are the steps drug development following lead discover and drug design

A
  • acquisition of patent
  • preclinical trials
  • development of an effective manufacturing process
  • clinical trials
19
Q

What are preclinical trials

A
  • these include investigations of drug metabolism, toxicology and formulation
20
Q

What are phase 1 drug drug trials

A
  • on a small group of healthy male volunteers 30-100 individuals
  • to determine safety, tolerability and pharmacokinetics
21
Q

Describe phase 2 trials

A
  • on a larger group 200-300 patients
  • designed to discover the efficacy of the drug in human patients
  • also any toxic side effects
22
Q

What are potential sources of lead discovery

A
  • natural products: plants , animals, microorganisms, and marine organisms
  • structural alteration of the natural substrate or ligand
  • parallel and combinatorial synthesis
  • synthetic libraries
  • me too drugs
  • computer aided design
23
Q

Describe secondary metabolites

A
  • often unique to a particular organisms or a small number of closely related organisms generally have no apparent utility to the organisms concerned
24
Q

Give an example of lead discovery by structural alteration of the natural substrate or ligand

A
  • adrenaline and noradrenaline were used as lead compounds in the development of salbutamol and dobutamine
25
Q

What is parallel synthesis

A
  • a relatively small scale technique
  • has been developed for the concurrent synthesis of large numbers of discrete single molecules
  • usually takes advantage of multiplace carousels with 6 or 12 vessels
26
Q

What is combinatorial synthesis

A
  • less favoured
  • small-scale technique used to generate large numbers of different compounds at the same time
  • usually generates mixtures of compounds this can lead to difficulties in discovering the identity of lead compound candidates
27
Q

What are synthetic libraries

A
  • libraries of compounds that can be used as a source of lead compounds
  • usually used when a new drug target is selected by a company
  • a problem with this is companies libraries do not tend to be diverse and my contain many groups of structurally related compounds
  • this is overcome by buying in libraries from specialist companies or academic institutions
28
Q

What are me too drugs

A
  • drugs already of the market used by competitor companies as lead compounds in their own drug discovery programmes
  • e.g. The antihypertensive agent captopril was used by two companies as a lead compound in their own drug discovery programmes leading to the production of two related antihypertensives
29
Q

What is computer-aided design

A
  • in situations where for example X-Ray crystallographic dats of a drug binding site is available, molecular modelling computer programmes can be used to design potential lead compounds
30
Q

What is cholesterol

A
  • a biosynthetic precursor to steroid hormones
  • an important component of cell membranes vital to normal cell function
  • synthesised in a complex series of enzyme catalysed transformations
31
Q

What is the rate determining step of the cholesterol biosynthetic pathway and what enzyme catalyses it

A
  • rate determining step is the reduction of HMG-CoA to mevalonate
  • catalysed by HMG CoA reductase
32
Q

In the development of statins to control cholesterol what was the drug target

A
  • HMG-CoA reductase
33
Q

What potential avenue for lead compound did researchers focus on and why in the development of a drug that controls cholesterol

A
  • secondary metabolites produced by microorganisms
  • because microorganism often produce chemicals toxic to other microorganisms to gain an evolutionary advantage
  • ## microorganisms lacking HMG-CoA reductase were predicted to produce inhibitors of the enzyme that would be toxic o microorganism dependent on it
34
Q

What is a type 1 statin and give an example

A
  • derived directly or indirectly from fungal metabolite s
  • also share the common structural feature of a southern hydrophobic decalin moiety and a polar norther fragment
  • example lovastatin

Contemporary Themes (4 decks)

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