B1一 Enzymes greater the concentration of the inhibitor, the less chance there is for ubstrate to enter the active site. Conversely, the greater the concentration of natural substrate the less efficient is the inhibition Inhibitor C No reaction Fig 9. Competitive inhibition. Noncompetitive inhibitors do not compete with the natural substrate for the active site. Such inhibitors usually bind to a different region of the enzyme and in doing so produce an induced fit, which changes the enzyme s shape such that the active site is no longer recognizable to the substrate (Fig. 10). Increasing the mount of substrate will have no effect on the level of inhibition Active site Induced Fig 10. Noncompetitive inhibition The binding site used by a noncompetitive inhibitor is called an allosteric site nd is often present in an enzyme at the start of a biosynthetic pathway(fig. 11) The allosteric site binds the final product of the pathway and provides a feed y allosteric site is unoccupied and the enzyme is active. When levels are high, the allosteric site is occupied, thus switching off the enzyme and the biosynthesis Thus, the final biosynthetic product can be used as a lead compound for the design of inhibitors that will bind to an allosteric site. Both competitive and noncompetitive inhibitors can be reversible or irre- versible. Reversible inhibitors interact with an enzyme through noncovalent
Section B- Drug targ intermolecular interactions (i.e. hydrogen bonding, ionic bonding and van der Waals interactions). There is an equilibrium between the enzyme-inhibitor complex and the free enzyme and unbound inhibitor. The position of the equi- librium will depend on the strength of the intermolecular interactions. If the intermolecular interactions are extremely strong, the equilibrium could be so far over to the enzyme-inhibitor complex that inhibition is effectively irreversible Irreversible inhibitors generally contain reactive electrophilic groups which are susceptible to attack from nucleophilic amino acids present in the enzyme, esulting in the formation of covalent bonds(ig. 12). Such bonds are strong and not easily broken and the enzyme remains permanently blocked. The only way that the body can sort out this problem is to degrade the enzyme-inhibitor complex and to synthesize new enzyme Covalent link Fig. 12. Irreversible inhibition Inhibitors should be as selective as possible for the target enzyme in order to avoid side effects. There are also several instances where a particular enzyme can ist in different forms known as isozymes. The catalytic reaction is identical, but the amino acid composition between isozymes is slightly different. If this varia- tion is in the binding site, it is possible to design drugs that will be isozyme- selective. Specific isozymes are more prevalent in one type of cell or tissue han another, so an isozyme-selective inhibitor is more likely to have a specific effect and have fewer side effects
Section B- Drug targets B2 RECEPTORS Key Notes Receptors Most receptors are proteins that traverse the cell membrane with a binding site on the extracellular region. Binding of a chemical messenger causes the receptor to change shape, initiating a process that results in message being received by the cell. The messenger does not undergo any eaction and departs unchanged, allowing the receptor to reform its Chemical Chemical messengers are neurotransmitters or hormones. messengers Neurotransmitters are released by nerves to interact with specific target cells and are short lived. Hormones are released by glands and travel round the body to interact with all the receptors that recognize them ing site The binding site of a receptor is the equivalent of an enzyme' s active site, but has no catalytic activit subr pes and Different receptors have different binding sites and interact with different chemical messengers. Each receptor can exist as various types and subtypes, which vary in concentration between different organs and tissues. This allows the design of drugs that are tissue selective Agonists mimic a receptors chemical messenger. Antagonists bind to a receptor but do not activate it. By binding to the receptor, they prevent activation by the natural messenger side effects Side-effects arise if a drug interacts with more than one receptor type or subtype There are three families of membrane-bound receptor Ligand-gated ion Ligand-gated ion channel receptors are part of a protein complex called channel receptors an ion channel. When a ligand binds to the receptor, the resulting induced fit causes the ion channel to open, allowing ions to flow through the channel for as long as the messenger is bound G-protein-coupled G-protein-coupled receptors activate signal proteins called G proteins receptors The G protein fragments to release a subunit,which binds to adenylate cyclase. The enzyme is activated or deactivated depending on the nature of the original G protein, and catalyzes the conversion of ATP to cyclic AMP, which acts as a secondary messenger and initiates a signaling cascade within the cell. A second form of signal transduction involves phospholipase C, which catalyzes the hydrolysis of a cell membrane lipid to two secondary messengers which initiate signaling cascades of their own
Section B-Drug targets Tyrosine kinase-linked receptors are proteins that act both as receptor linked receptors and enzyme Binding of a chemical messenger activates a kinase enzyme on the intracellular region of the protein, resulting in the phosphorylation of tyrosine residues. These regions act as binding sites for signal proteins and enzymes, initiating a signaling cascade which ultimately results in gene expression and protein synthesis ceptors are present within the cell and so the chemical messenger hydrophobic to cross the cell membrane. Activation of the and switches on transcription, leading to the synthesis of proteins Related toplcs Enzymes(b1) Functional groups as binding groups( G3) Binding interactions(G2) Epidermal growth factor receptor (L1) Receptors are proteins that are crucial to the body s communication process. They act as the cells ' letter boxes and receive messages from chemical messen- gers embedded in the cell membrane, traversing it such that there are extracellular and intracellular regions (Fig. 1). On the extracellular region, there is a hollow, or cleft, called the binding site. Chemical messengers fit into these binding sites and are bound by intermolecular forces in the same way that substrates are bound to the active sites of enzymes. Similarly, the binding process involves an induced fit whereby the receptor alters shape to accommodate the messenger However, unlike enzymes, no reaction takes place. The messenger binds, but since this is an equilibrium process, it can depart again unchanged, allowing the receptor to return to its original shape. This might appear to be a pointless ise, but the change of shape induced by bindir which results in a message being transmitted into the cell. Thus, the chemical messenger gives a message to a cell without entering the cell. This will be covered in more detail below. The study of how drugs interact with receptors is Chemical messengers can be classed as neurotransmitters or hormones messengers Neurotransmitters are released from nerve endings and are crucial to the Depar Fig. 1. Membrane bound receptors
mechanism by which nerves transmit messages to cells (Fig. 2). Nerves do not make direct contact with their target cells and the separation between them is called the synaptic gap. When a nerve is active, it releases a neurotransmitter which diffuses across the synaptic gap and binds with a receptor in the cell membrane of the target cell Nerve Nerve Neurotransmitter Induced fit membrane membrane Tar Fig. 2. Neurotransmission Neurotransmitters are usually small molecules, such as acetylcholine, norep nephrine (noradrenaline), dopamine and serotonin (Fig. 3). They bind briefly to their target receptor, pass on their message and depart unchanged to be quickly deactivated such that the message is only received once. This deactivation also means that neurotransmitters do not activate receptors on more distant cells R=H NorepInephrine(Noradrenaline) Dopamine R=Me Epinephrine(AdrenalIne) Fig 3. Neurotransmitters and hormones Hormones are chemicals released from glands or cells that enter the blood stream in order to travel round the body, activating all the receptors that recog nize them. Since they have long journeys to undertake, they are not swiftly deactivated. Epinephrine (or adrenaline) is a hormone released from the adrenal medulla in situations of stress or danger, and which prepares the body for physical exercise. Other examples include the steroids, which have diverse actions in the body. The mechanism by which a receptor is activated is the same regardless of whether the messenger is a neurotransmitter or a hormone. In both cases, the chemical messenger binds to the receptor and causes it to change shape, resulting in a message being received by the cell BInding slte The binding site of a receptor is the equivalent of an enzyme's active site. The binding process is also identical, involving the same kind of intermolecular binding forces and induced fit. However, the binding site of a receptor does not catalyze any reaction and the messenger can depart unchanged