Drug Structure, Function & Properties PDF

Drug Structure, Function & Properties Dr Lynda Storey X2528 ([email protected])  Learning Objectives 1. Identify functional groups in drug molecules 2. Identify other important features e.g. stereochemical properties within drug structures 3. Relate 1 & 2...

Drug Structure, Function & Properties Dr Lynda Storey X2528 ([email protected])  Learning Objectives 1. Identify functional groups in drug molecules 2. Identify other important features e.g. stereochemical properties within drug structures 3. Relate 1 & 2 to the properties of drugs. 4. Recognise and describe the binding forces that operate between drug molecules and targets (active sites). Text Book An Introduction to Medicinal Chemistry – Graham L. Patrick  Aims for Lecture 1 1. Gain a general understanding of how and where drugs interact. 2. Have an appreciation for protein structure. 3. Know the forces involved in controlling protein structure. So far in semester 1 and semester 2 (PH1015): General structural properties of molecules Bonding and hybridisation Aliphatic functional groups Stereochemistry Aromatics Heterocyclics Let us remember one thing: drugs are molecules too! They happen to have an effect on the body! If we can recognise the functional groups present in a drug structure we can: Predict its chemical properties: Solubility Reactivity and stability Ionisation characteristics Acid/basic properties Being able to recognise functional groups also enables us to: Predict the absorption in the body Predict possible activity in the body Obviously vital with drug molecules.  How Do Drugs Work? Looking at it most simplistically: The drug is administered: - Swallowed, injected, inhaled, applied, inserted... The drug travels to its site of activity. At the site of activity the drug interacts with a target. The drug/target combination “triggers” a biological response.  DRUG ABSORPTION, DISTRIBUTION, METABOLISM & EXCRETION TRANSDERMAL SUBCUTANEOUS BUCCAL RECTAL INTRAVENOUS ORAL SUBLINGUAL TOPICAL INTRAMUSCULAR TISSUE GASTRO- INTESTINAL DIFFUSION/ABSORPTION TRACT BLOOD LIVER DISTRIBUTION METABOLISM DRUG TARGET TISSUE KIDNEY RECEPTOR DIFFUSION/ INTERACTION EXCRETION ABSORPTION Reproduced from “Drugs – From Discovery to Approval” by Rick Ng, 2004, John Wiley & Sons, Inc., New Jersey. TRANSPORT MECHANISM Except for intravenous injection, drug molecules usually have to cross cell membranes to reach target sites. There are four basic transport mechanisms: Passive diffusion Directed Facilitated diffusion Study: Define these Active transport transport mechanisms. Pinocytosis  Where Do Drugs Work Clearly, since life is made up of cells, then drugs must act on cells!  Where Do Drugs Work Lipids can act as drug targets Carbohydrates can act as drug targets Proteins can act as drug targets Nature of the target: The vast majority of drug targets are proteins & nucleic acids. Many are found in membranes of cells. Often only a particular area of the protein will interact with the drug molecule.  Protein Structure Primary (1) Structure – Simply the order of individual amino acids held together by peptide bonds Secondary (2 ) Structure – Alpha helix – coiling held together by H-bonds – Beta-pleated sheets – layering held by H-bonds Tertiary (3 ) Structure – Overall 3D structure, a consequence of the 1 structure, crucial to function & interaction with drugs.  Protein 3 Structure Held together due to attraction & repulsion until the most favourable shape is found. Four types to consider: – Covalent: the strongest (e.g. disulphide b/w 2 cysteine residues. – Ionic: strong bonding force between groups with different charges (e.g. carboxylate & ammonium). – Hydrogen: formed between electronegative atoms & protons (e.g. alcohol to alcohol) – Van der Waals: weakest, interaction b/w hydrophobic molecules (e.g. aromatic residues such as phenylalanine)  CH H2C CO2 S S H2 C H3N CH Forces producing the H tertiary structure O H O So in a very small region (the binding site) of this enormous structure, the drug can bind. Remember: as well as membrane proteins, other structures, such as: enzymes nucleic acids lipids carbohydrates can act as targets for some drugs as well. As we shall see, a number of structural features allow the combination of drug and target. Binding interactions between drugs and their targets The functional group structure determines the properties of a molecule. One of these properties is the ability to intermolecularly bond to another molecule. These forces of attraction are fundamentally important for drug - target combinations. What can happen between molecules in a beaker can happen at cellular level as well These forces are the same as those controlling protein 3 structure. ionic interactions hydrogen bonding van der Waals interactions dipole-dipole interactions covalent bonding Usually the first 4 types account for the drug/target combination – these tend to be reversible interactions. Covalent bonds also form but are more unusual – they are also usually (but not always) irreversible.  Summary 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.