Drug Structure, Function & Properties Lecture 3 PDF

Drug Structure, Function & Properties Lecture 3  Summary of Lecture 2 Covalent, ionic, ion-dipole, H-bonding and van der Waals forces may all play a part in drug-target interactions. Hydrogen bonding involves both HBDs & HBAs. Ethers are not HBDs and are poor HBAs. Bonding...

Drug Structure, Function & Properties Lecture 3  Summary of Lecture 2 Covalent, ionic, ion-dipole, H-bonding and van der Waals forces may all play a part in drug-target interactions. Hydrogen bonding involves both HBDs & HBAs. Ethers are not HBDs and are poor HBAs. Bonding interactions of oxamniquine. Ionic CH3 H2 H2C N CH CH3 HN Hydrogen bonding O2N H2C Van der Waals OH Target receptor  Aims for Lecture 3 1. Gain an understanding of Structure/Activity Relationships. 2. Build on the knowledge of HBDs & HBAs by applying it to the following functional groups: amines carbonyl groups: aldehydes ketones esters carboxylic acids  Drug Discovery & Drug Development Past: Pre 20th Century - herbs, potions Isolation of active ingredient Structure determination General principles developed Present: -Choose a disease -Choose a target -Identify a bioassay -Find “lead” compound -Isolate & purify lead -Determine structure of lead -Identify SARs -Identify pharmacophore -Improve interactions -Improve pharmacokinetics -Patent the drug -Study drug metabolism -Test for toxicity -Design a manufacturing process -Carry out clinical trials -Market the drug -Make Money!!!  Pharmacophores When looking at the pharmacological activity of drugs the first “starting drug” is called the lead compound The lead compound shows biological activity when it interacts with its target: – The activity may not be very great – There may be undesirable side-effects By making analogues of the lead compound we can then tell which parts of the molecule are necessary for binding/activity The pharmacophore of a drug defines the important functional groups that are required for binding/activity Structure-Activity Relationships (SARs) Aim: To discover which parts of the molecule are important for biological activity & which are not. How? By making small variations from the original structure.  SARs can be summarised: Drug with activity Change one functional group to another Modified drug structure The modified structure is then re-tested for activity: If still as active, then the original functional group is unimportant X or If activity falls, then the original functional group is important to binding  More on HBD’s & HBA’s We have seen Hydrogen Bond Donors (HBD) and acceptors (HBA) in terms of alcohols & phenols (see previous lecture) But there are others! Amines Often at physiological pH, amines are ionised (protonated). They can then ionically bond with a COO¯ group in the target (see adrenaline earlier).  If they are not ionised at physiological pH, 1º and 2º amines can bind by H-bonding (as HBDs) 1º , 2º and 3º amines can bind by H-bonding (as HBAs). To test whether amine binding is important for a drug, we can convert it to the amide. Drug Drug O C NH2R N CH3 R CO2 CO2 Ionic interaction No interaction! Target Target  For H-bonding we have: HBD Drug HBA Drug H N H N H R X X R Target Target Again conversion to the amide will prevent H- bonding (either as donor or acceptor)  Aldehyde and Ketones These both contain polarised carbonyl groups    Drug  O  C O   Dipole-dipole   interaction Target It is thought that the dipole in the C=O bond may play a part in drug/target interactions. However, H-bond formation with the carbonyl oxygen acting as HBA is common with targets: Drug O H X Target  To test whether the C=O group is important in binding, it is reduced to the corresponding alcohol. This would change the geometry of this area of the drug (i.e. change a planar sp2 hybrid to a tetrahedral sp3 hybrid). This would have an effect on the dipole-dipole interaction. Reduction to an alcohol may also affect the ability to act as a HBA. reduction H Drug O Drug H X OH Target May now be too far away to act as HBA Further conversion to an ether (see lecture 2) would also be worthwhile.  Esters This is a common group in drugs They can act as HBAs with target molecules. However, in the body they are rapidly hydrolysed. Esters are normally made to mask a polar group (e.g. an alcohol or phenol or carboxylic acid). Being less polar, esters will cross fatty barriers (e.g. the gut wall) much more easily. Then, in the blood they are hydrolysed to the active drug (e.g. alcohol or phenol etc.) Compounds acting in this way are called prodrugs  With an ester: Drug O C R O prodrug hydrolysis Drug O Fatty barrier C R (e.g. cell membrane) O Drug O C H O drug  Carboxylic Acids These can interact by ionic bonding or by H-bonding (as both HBA and HBD). With ionic interactions we have: Drug O C O NHR2 Target  H-bonding is possible in many ways (as HBD and HBA) Drug As HBA we have: O C Drug O H C O H O H X H X Target Drug O Target C As HBD we have: O H X Target  The importance of carboxylic binding can be tested by conversion to an ester. Esters cannot ionically bind nor can they act as HBDs. May have a steric effect on HBA ability as well.  Alkenes & Aromatics Van der Waals forces are the interactions between these and flat hydrophobic regions of the binding site. Drug Good Interaction redu c ti o n Drug Flat Hydrophobic Region H H Poor Interaction  Summary of Lecture 3 SARs: involves working out which functional groups are essential for activity by making small modifications to the lead compound. Amines can interact with targets through ionic bonds and through H-bonding as both HBDs & HBAs. Carbonyl groups act as HBAs. Esters are often used in the formation of prodrugs in order to cross membranes. To test the SAR of aromatic groups, they can be changed to aliphatic groups. Directed Study for Lecture 3: Drug Structure, Function & Properties On the following structures: i) circle the functional groups that could help bind the molecule to a receptor site in the body; ii) describe the binding interaction of the functional groups that you circled. Binding interactions: HO O N CH3 H HO H O N NEt2 OCH3 Cl NH2 Binding interactions: OCH2CF3 CH3 O H S N N N CH3 O N N H CO2H OH O HO NH2 H N CO2H O OH