Drug discovery 6b Flashcards
why is conformation of a drug important ?
it determines whether it will be a good drug
what bond angle is present in a tetrahedral shaped molecule ?
109.5 degrees
what can all single covalent bonds do ?
spin
- no effect for carbon-hydrogen bonds
- when the central carbon- carbon bond in ethane spins the position of the hydrogen bonds change - this means you get different conformations of the molecule
what is newmans projection ?
projection looking down carbon carbon bond
- it is a way of defining rotation about a single bond
what does the dihedral angle (torsion angle) permit ?
means you can define the conformation around that bond
what is the conformation in ethane when the hydrogens at the back are maximally separated from those at the front ?
staggered conformation so the bond angle is 60 degrees
what are the varying conformations of butane ?
when looking down the central carbons the methyl groups can be on the same side where the terminal methyl groups are closest= high energy state and they can be on opposite sides in which the termina methyl groups are furthest away from each other producing a low energy state
- also high energy when there is a clash between a terminal methyl and a terminal hydrogen
what is the bond angle when the 2 bulk methyl groups in butane are maximally separated ?
180 degrees
what is the bond angle of butane in the anti and gauche state ?
anti- 180 degrees
gauche- 60 degrees
what conformation does the butane molecule prefer to be in ?
prefers to be in one of the 3 lowest energy conformations anti or gauche
- anti is sometime referred to as trans
- this enables a choice of conformation for each single bond but also some restraint
in butane what can constrain conformational flexibility ?
constrained by adding in ring systems
why are there 2 isomers of butene ?
because it contains a double bond and therefore it cannot rotate
- cis and trans conformations
what is the bond angle when a nitrogen forms a quarternary ammonium ion ?
109.5
what conformational shape is cyclohexane ?
it is puckered and can form boat or chair conformation
- often an oxygen or nitrogen are inserted into this kind of puckered ring system e.g. glucose
which conformation of cyclohexane is more stable ?
chair conformation is the most stable
there are different conformations of acetylcholine so how did they determine which one was bioactive ?
achieved by restricting the conformation acetylcholine by inserting a cyclopropane ring into the middle of the molecule
- this resulted in analogues which mimic versions of acetylcholine that dont have a rotatable central carbon carbon bond
what is cyclopropane ?
its an odd molecule - triangle shape
ring system forces bonds angles to be 60 degrees which is a long way from the ideal 109.5
therefore it is rather unstable
using cyclopropane to restrict acetylcholine into specific conformations enable the determination of the active form. which form was the active one ?
the trans version - only one of them - the active version was equivalent to a conformtion of ach with a 137 dihedral angle therefore not what we would consider to be the most stable conformation
cis isomers were inactive
when was the M2 muscarninc acetylcholine receptor x ray structure determined?
25/1/12
but the ligand to it was an antagonist- QNB
what do functional groups in organic compounds do ?
they form main interactions with drug target
impart certain properties to a compound
what does the hydroxyl group in an organic compound do ?
does not ionise - doesnt form a hydroxide ion or release a proton
it can form hydrogen bonds
what are organic compounds that contain a hydroxyl group called ?
alcohols
what properties do hydroxyl groups have ?
they are polar and can form hydrogen bonds - therefore important for drug interactions
what is an example of how hydroxyl groups form drug-target interactions ?
catechol hydroxyl groups of isoprenalin
what is a carbonyl group ?
carbon with a double bond to an oxygen and then 2 single bonds to 2 other groups
in a carbonyl group if the 2 single bonds to are to carbon atoms, what is produced ?
a ketone
in a carbonyl group if one of the single bonds is to a hydrogen what is produced ?
an aldehyde
in the carbonyl group what property does the carbon-oxygen double bond possess and what can it do ?
it is polar and it can accept a hydrogen bond
what can the carboxyl group do ?
it can ionize
- it releases a proton and is therefore an acid
- the proton from the OH group can dissociate and form and negatively charged molecule- this is important as you may then be able to form electrostatic bonds
what can amino/amine groups do ?t
they can bind protons
- nitrogen atom becomes positively charged
- when 4 protons are attached it forms a quarternary amine which is positively charged - this means the receptor is negatively charged
in an amino/amine group, what can the lone pair on the nitrogen do ?
it can be shared with a proton to form a coordinated covalent bond - this causes the nitrogen to gain a positive charge
what can the amide group do ?
it CANNOT ionize
but they are polar and can form hydrogen bonds
describe the characteristics of the central carbon in an amide group :
it is trigonal planar
double bond is delocalised so that the carbon-nitrogen bond has some double bond character
what are most drug targets ?
proteins
what are proteins made up of ?
amino acids
backbone consisting of an amino group and a carboxyl group separated by a carbon - the alpha carbon
how are the 20 naturally occuring amino acids distinguished?
distinguished by the nature of their side chain, the moiety attached to the alpha carbon
what isomers are all the naturally occurring amino acids ?
L-isomers
what are the different classes which the amino acids fall into ?
no R sulphur aliphatic aromatic charged polar tethered
what amino acid has no side chain ?
glycine
what amino acids are in the sulphur class?
cysteine
methionine
what amino acids are in the aliphatic class?
alanine
valine
leucine
isoleucine
what amino acids fall into the aromatic class ?
phenylalanine
tyrosine
trytophan
histidine
what amino acids fall into the charged class ?
aspartic acid glutamic acid arginine lyseine histidine
what amino acids fall into the polar class ?
serine
threonine
glutamine
asparagine
what amino acid falls into the tethered class ?
proline
how are amino acids linked together ?
by peptide bonds= covalent bonds
the end with the amino group= n terminus
end with the carboxylic acid group= c terminus
formation of the peptide bond results in amide
why dont peptide bonds rotate ?
because it is an amide group
it has partial double bond character due to the delocalisation of the electrons
it is usually fixed in the trans conformation
what shape are the amide groups ?
planar
how are secondary structures and proteins folds produced in proteins ?
the peptide bonds cannot rotate so they confer little flexibility
it is the other bonds in the main chain that can rotate and produce secondary structure and protein folds
- like in butane there are 3 main conformations for each bond but the final conformation will depend on the global stability of the protein fold as a whole
