Drug Structure, Function & Properties Lecture 2 PDF

Drug Structure, Function & Properties Lecture 2  Summary of Lecture 1 Many drugs have to cross cell membranes. Lipids, carbohydrates, proteins & nucleic acids are all drug targets. Proteins & nucleic acids are the most common type of drug target. Protein 3 structure is depen...

Drug Structure, Function & Properties Lecture 2  Summary of Lecture 1 Many drugs have to cross cell membranes. Lipids, carbohydrates, proteins & nucleic acids are all drug targets. Proteins & nucleic acids are the most common type of drug target. Protein 3 structure is dependent upon intramolecular bonding forces. These same forces are responsible for drug-target interactions.  Aims for Lecture 2 1. Differentiate between the different types of bonding forces between drugs and targets. 2. Recognise hydrogen bond donors/acceptors. 3. Evaluate different functional groups as hydrogen bond donors/acceptors.  Binding Sites Model of drug-target binding interaction  Binding Sites Active Site Drug Active Site Response Target The active site has to be on or near the surface. The site could be a groove, a hollow, or a gully. It’s just like a “lock” and the drug is the “key”.  Covalent Bonds These are relatively rare, but do occur. Amine groups are good nucleophiles & can react with electrophilic structures in a molecule.   H R NH2 C X R N C This can occur with, for example, alkyl halides. As a result of this reaction a covalent bond is formed.  Covalent Bonds Covalent bonds are the strongest bonding force available. Two thiols which are close together can form a covalent disulphide bond as a result of oxidation. Bond Strengths: (S-S) = 250 kJ mol-1 Bond Bond strength, kJ mol–1 C-H 440 N-H 450 O-H 500 C-C 348 C-O 358  Ionic Bonds Opposite charges attract! Ionic interactions can be effective at a distance further than those required for other types of interactions, and they can persist for longer. Many drugs contain an amine H (basic) group. N CH3 At physiological pH these groups will be ionised. H H It is thought that adrenaline and R N H CH3 noradrenaline “dock” with their targets using a COO– group on the CO2 target: Target  Ionic Bonds Acid groups, such as carboxylic acid side chains of aspartic acid and glutamic acid, are deprotonated to give anionic groups. O O N H2N H H N O Pivagabine- H2N antidepressant Target Bond Strength = 20 kJ mol-1 Ion-Dipole & Dipole-Dipole Interactions (van der Waals) These are to do with polarisation of bonds in functional groups and so are dependent upon electronegative atoms (such as S, O, N). This results in an asymmetric Target distribution of electrons. H3N Od- R' R d+ O  Hydrogen Bonds Hydrogen bonds are a type of dipole- dipole interaction formed between the proton of a group X-H, where X is an electronegative atom, and other electronegative atoms (Y) containing a lone pair of electrons. X & Y are usually N, O, or F. The hydrogen bond is unique to hydrogen because it can carry a positive charge at physiological pH while remaining covalently bonded in a molecule. Bond Strength = 7-40 kJ mol-1  Hydrogen Bonds We have seen how important these bonds are with water solubility, effect on boiling point etc. The H-bond donor (HBD) (X-H) contains the H atom. The H-bond acceptor (HBA) (Y) is the electronegative element that interacts with it. Adrenaline contains two phenolic OH groups and these H-bond to its target. H O O H Target O H O H Adrenaline Salicylic Acid: O H O O H O H Target Although they are not as strong as ionic bonds, H-bonding is very common and important. Alcohols & Phenols These are very common functional groups in drugs. They are generally involved in the formation of H- bonds. They can act as both HBDs and HBAs in their interaction. If the drug is acting as a HBD we would have: drug X H O target If the drug was acting as HBA: drug O H H X target To modify the OH group to see whether it is required for binding (either as HBD or HBA): change to an ether functional group change to an ester functional group Ethers cannot act as HBDs: Ether group drug Me X O Not a HBD! target Ethers are poor HBAs due to steric hinderance! drug H H C Poor HBA O H H X target Induced dipole – Induced dipole Also known as: London Dispersion Forces Remember, these involve non-polar groups/molecules. Most important for drug molecules containing: – aromatic rings – alkyl groups (aliphatic side chains) Again looking at adrenaline, it has an aromatic ring. This can form van der Waals interactions with an aromatic ring in the target: target van der Waals attraction (London Dispersion Forces) Aromatic ring of adrenaline So for the adrenaline molecule : XH OH H H H O N O H CH3 O H O CO2 H Target With the adrenaline structure, several parts of the molecule interact with particular areas of the target. Multiple interactions are very common with drugs.  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. Directed Study for Lecture 2: Drug Structure, Function & Properties The following questions relate to Oxamniquine, an important Developing World drug used to treat schistosomiasis, which is pictured on the following slide. Q1. Why is the aliphatic amine ionised? Q2. Describe all of the bonding interactions that may occur between the drug and its target. Q3. How would you determine whether the hydroxymethylene group was essential for activity? Bonding interactions of oxamniquine. CH3 H2 H2C N CH CH3 HN O2N H2C OH Target receptor