Medicinal Chemistry Tutorial Notes

1. What is medicinal chemistry? How a drug binds to its target 2. What does a drug • The drug needs to be the right shape to fit into the binding need to bind to a site of the protein protein? • The drug needs to stick to the protein in some way The drug molecule needs to have the right shape SO THAT the functional groups can make these interactions with the protein (chirality), to allow it to stick to the protein well 3. How are drug molecules shaped? • Molecules have different shapes, which are drawn in specific ways (check goodnotes or e-lecture) • Bonds rotate so that certain groups can be as far apart as possible • Molecules are either configurations or conformations of each other 4. What are confor- Some molecules are conformations of each other, which mations? means they are different shapes of the same molecule and you can get from one to the other without breaking a bond eg through rotating a bond 5. What are config- • Some molecules are configurations of each other, which urations? means there is a different spatial arrangement of atoms or groups around a central atom in a molecule, and you cannot get from one to the other without breaking a bond. • These types of molecules form enantiomers which are non-superimposable mirror images of each other. Usually only one of the enantiomers of the drug can fit into the receptor sites on the protein. The binding sites have information about different enantiomers coded into them. • Any change in chirality may mean that the bonds needed to bind to the protein cannot form 6. How are 6 • Cyclohexane: If cyclohexane was flat then all the angles membered rings in the flat hexagon would be 120°, however all of the carbons in cyclohexane are sp3 hybridised, which means 1/7 eg cyclohexane shaped? the four bonds of carbon, that are single bonds, are formed by mixing one s orbital and three p orbitals. These bonds have bond angles of 109° therefore cyclohexane cannot be flat, so has a distinct 3D shape • Benzene: Benzene rings are flat/ planar, to allow for delocalisation to extend between each ring. 7. What types of conformations can cyclohexane and other similar cyclic molecules form? • A chair conformation, which is favourable because the hydrogens sit comfortably • A boat conformation, which isn't favourable as the hydrogen atoms crash into each other - therefore cyclohexane sits as the chair conformation and not the boat conformation • Substituents on the cyclohexane ring sit as far apart as possible • An example in medicine: Donepezil contains a 6-membered ring (not cyclohexane since it contains a nitrogen) in the middle of the molecule, which adopts the chair conformation when bound to its protein target, with groups laid out far apart from each other. This helps it make some favourable interactions with its target 8. How do shapes of similar and different molecules compare to each other? (idk how to word this question) Molecules that look similar can have different shapes: • Two benzene rings joined together by a carbon-carbon bond is flat • One benzene ring attached to a cyclohexane by a carbon-carbon bond has a different shape: the cyclohexane adopts a chair shape and the benzene sits away from the cyclohexane. Molecules that look different can have similar shapes: • Two benzene rings joined by a carbon-carbon bond is flat • One benzene ring attached to a pyridine ring by a single bond is also flat • One benzene ring attached to a pyridazine by a single bond is also flat • These are all the same shape as each other, and they are called bioisosteres 2/7 9. How do drugs stick to the protein after initially binding? • The drug molecule doesn't usually covalently bond to the protein - Some useful drugs do form covalent bonds eg activated omeprazole covalently bonds to the proton pump in the stomach - However some drugs are toxic because they form covalent bonds to the protein • Ionic interactions (electrostatic attraction) between the drug and protein - strongest form of bonding - occurs in amine functional groups, as amines are basic so they exist in the body as NH3+ • Hydrogen bonding • Van der Waals - weakest form of bonding - occurs in areas of the molecule with dense C and H atoms • The drug needs to have the right functional groups, as these groups will interact with side chains of the amino acid in the protein through ionic interactions, hydrogen bonding or Van der Waals forces, to allow the drug to stick to the protein • The more interactions the drug makes with the protein, the better it sticks, which means a lower ”G and a lower IC50 10. What are some medicinal examples of drugs binding to proteins? • There are two aromatic rings in Donepezil which are stacked against two different aromatic rings in the tryptophan residue. This interaction is a subset of Van der Waals called pi-pi stacking. • Rosuvastatin inhibits synthesis of cholesterol in the body by binding to a protein. It contains two chiral centres, two alcohol groups, a carboxylic acid, an alkene, a sulfanamide and two aromatic rings. - it binds to a protein by hydrogen bonds- the COOH with a OH on the protein, and the OHs with hydrogen on amino acid side chains on the protein - if the two hydroxy groups were methyls, the hydrogen bonds wouldn't be able to form since methyl groups cannot 3/7 form hydrogen bonds - if the two hydroxy groups had the opposite chilarity (if the groups were pointing away from us rather than towards us), the hydrogen bonds wouldn't be able to form because the groups would be too far away to form the attraction 11. What are medicinal examples of when chirality matters, and when it doesn't matter? • In thalidomide, chirality makes a huge difference, as one enantiomer treats morning sickness but the other enantiomer causes fetal malformation. • In ibuprofen, chirality doesn't matter, since one enantiomer is active and the other enantiomer is inactive, but harmless, so has no good or bad effect in the body. - Ibuprofen is given OTC as a racemic mixture. It used to be made as just the active enantiomer aswell, which is more expensive, however it stopped being made since it takes more effort to formulate but doesn't have much more difference than just giving the racemate. 12. What is polarity? • A molecule in which the electrical charges are unevenly distributed- the electrons are not evenly shared between the atoms. The polarity of a molecule depends on the balance of polar and non-polar bond within the molecule • Bonds between carbon (or hydrogen) atoms and nitrogen or oxygen are polar eg C-O, O-H, C-N, N-H • Polar bonds are hydrophilic, since water is a polar molecule so is attracted to other polar molecules. • Polar compounds dissolve in polar solvents like water • Bonds between carbon atoms or carbon and hydrogen atoms are non-polar • Non- polar bonds are lipophilic • Non polar compounds dissolve in nonpolar solvents like petrol or diethylether • Polar and non polar compounds do not mix eg water and oil 13. What is drug me- The body recognises drugs as being foreign substances tabolism? and therefore tries to get rid of them, usually through the urine. To dissolve in the urine, the drug needs to be made into something that is mostly water-soluble, rather 4/7 than part water-soluble and part lipid-soluble. Therefore the body undergoes drug metabolism to alter the drugs so that they are water-soluble, allowing the drugs to be excreted. Some drugs are already water soluble so not much metabolism is necessary in these cases. 14. What are the four ADME stages of drug • Adsorption- how the drug gets from the site of administrametabolism? tion to the systemic circulation. The site of administration can be the GI tract for oral medicines, the skin for transdermal patches, muscle for some injections, buccal, nasal etc. This stage is ignored for intravenous administration • Distribution-how the circulation of blood distributes the drug around the body's tissues. This means the drug must be water-soluble to be in the blood, as the blood is mainly water. The drug must also be miscible with lipids to cross cell membranes, which are mostly made of lipids, and get into tissues. Here, the drug binds to proteins and has its effect • Metabolism-drug metabolism involves the active ingredient itself, excluding the excipients or capsule • Excretion- how the drug, or its metabolites (a chemical substance the body has made by undergoing metabolism), leave the body, and this is usually in the urine. Therefore the drug must be water-soluble to be able to exit the body 15. What are the two stages of how the drug is metabolised? Phase 1- functionalisation • The aim is to add or expose a polar functional group to the drug molecule • This can be done through - hydrolysis eg of an ester to a carboxylic acid and alcohol or of an amide to a carboxylic acid and an amine - dealkylation, which is removing a small alkyl group from a nitrogen or oxygen atom - oxidation eg converting an alcohol to an aldehyde, a C-C bond to a C=C bond, adding an OH group etc - reduction eg converting a carboxylic acid to an alcohol 5/7 Phase 2- conjugation • This adds a very polar molecule to an OH group in the drug or in a metabolite to allow it to be excreted in urine • This molecule is usually glucuronic acid (a sugar) but sulfate groups are also used - Glucuronic acid binds via hydrogen bonding, sulfate groups bind via covalent binding Sometimes, the process of drug metabolism stops after phase 1, or phase 1 doesn't happen at all and it goes straight to phase 2. 16. How is aspirin metabolised? 1. Functionalisation- the ester group in aspirin gets hydrolysed and therefore removed, so an OH group remains on the aspirin molecule. 2. Conjugation- the body breaks up the OH and adds a glucuronic acid molecule onto the O (the glucuronic acid molecule is shown as Gluc on a skeletal formula) 17. How is paracetamol metabolised? There are two different ways 1st way 1. No phase 1 2. Conjugation- a sulfate group is added to the OH group at the top of the molecule (sulfation) OR a glucuronic acid molecule is added to the OH group (glucaronidation) 2nd way 1. Functionalisation- the paracetamol molecule undergoes oxidation to form a reactive intermediate (a paracetamol metabolite) 2. Conjugation- this intermediate reacts with glutathione in the body (shown as G-S on skeletal formula), which has a free sulfur atom that forms a covalent bond to a carbon in paracetamol, forming a metabolite that can now be excreted However, covalent bonds in molecules generate toxicity. The body only has a certain amount of glutathione stored. The intermediate formed here can use up all the glu6/7 tathione in the body, leading to an absence of it in the body, causing hepatotoxicity, which damages the liver, and this can be fatal during overdose of paracetamol. Therefore the intermediate formed here is a toxic metabolite. 18. How is methamphetamine metabolised? 1. Funtionalisation- the methyl group at the end of the molecule is removed from the nitrogen atom to make the molecule more polar (dealkylation), forming amphetamine 2. Conjugation- through glucuronidation or sulfation 19. What are prodrugs? • A drug administered in an inactive/ weakly active form but is metabolised into an active form. • Normally, drugs undergo metabolism and become inactive and are excreted, however prodrugs need to undergo metabolism to become active • Examples include heroin and ramipril • Heroin is used for pain relief however it is inactive at all opioid receptors but is still an effective painkiller, since it can enter the CNS where the opioid receptors are, very rapidly due to it being more lipophilic. Once it reaches this point, it is metabolised into morphine, which then acts at the opioid receptors. 20. How is heroin metabolised? 1. Funtionalisation- it undergoes hydrolysis to form morphine, the active metabolite 2. Conjugation- morphine undergoes either glucuronidation or sulfation 21. How is ramipril metabolised? 1. Funtionalisation- the ester is hydrolysed into a carboxylic acid, forming ramiprilat, the active metabolite 2. Conjugation- glucuronidation 7/7