Principles Of Med Chem Flashcards
(34 cards)
1
Q
What is an alkaloid
A
- a basic N-containing natural product that excludes proteogenic amino acids and DNA/RNA bases
2
Q
What is a drug
A
- a compound that interacts with a biological system to induce a biological response
3
Q
Define the term therapeutic ratio
A
The ratio of maximally tolerated dose to the minimally curative or effective dose
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
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
6
Q
What is an organelle
A
- a membrane bound compartments or structures in a cell
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
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
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
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.
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
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
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
14
Q
What is Lipinski’s rule of 5 for good oral bioavailability of a drug candidate
A
1) drug molecular weight
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
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
What is parallel synthesis
- 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
What is combinatorial synthesis
- 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
What are synthetic libraries
- 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
What are me too drugs
- 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
What is computer-aided design
- 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
What is cholesterol
- 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
What is the rate determining step of the cholesterol biosynthetic pathway and what enzyme catalyses it
- rate determining step is the reduction of HMG-CoA to mevalonate
- catalysed by HMG CoA reductase
32
In the development of statins to control cholesterol what was the drug target
- HMG-CoA reductase
33
What potential avenue for lead compound did researchers focus on and why in the development of a drug that controls cholesterol
- 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
What is a type 1 statin and give an example
- 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
