A2- From concept to market structure that will interact with that target. Such a structure is known as a lead compound(Section E)and is the starting point for drug design. Phase 2-drug Once a lead compound has been identified, the medicinal chemist will devise design synthetic routes that will allow the synthesis of various analogs( Section F) Having produced a series of analogs, the activities of these compounds are compared and certain structural features that are more important to activity than others are identified (structure activity relationships-Section G). These features are retained in the design of further analogs, which will interact more effectively or more selectively with their target(Section H). As well as this, it is necessary to design analogs that have the correct pharmacokinetic properties to reach their Phase 3- drug As soon as a potentially useful drug is discovered, it is patented(Section D).The testing and potential drug must then be thoroughly tested for any side effects or toxicity so carried out to identify wh lites are formed. These metabolites are then tested for activity and side effects. If the drug passes these tests, it is put forward for clinical trials(Section K). Finally the drug can be marketed. At the same time as the pre-clinical and clinical trials are taking place, work is carried out to develop a large-scale synthesis of the compound(section D). The various tests and development work carried out on a new drug must be properly controlled and documented such that they adhere to the requirements laid down by the various regulatory authorities(Section K). Otherwise, the drug may not be allowed to enter clinical trials or the market. The chemlst's Chemists and medicinal chemists make important contributions at various contribution stages of the drug research program. The medicinal chemist is most involved ith drug discovery and drug design. Development chemists are involved in designing a large-scale synthesis for a drug. Organic synthetic chemists are involved in synthesizing radiolabeled drugs for drug metabolism studies, while analytical chemists are involved in quality control, ensuring that the drug satis- fies purity specifications. Many of the practical skills acquired in a chemistry or medicinal chemistry degree are invaluable to the pharmaceutical industry. Practical techniques such as extraction, chromatography, distillation and crystal- lization are vital if a lead compound is to be isolated and purified from a natural extract or a synthetic mixture. Synthetic skills are required in order to synthesize analogs of a lead compound in order to carry out structure activity relation ships. Analytical skills, such as the ability to interpret nuclear magnetic reso- nance (NMR) spectra, are important in determining the structure of a lead compound or a synthetic analog. These skills are just as relevant to the develop ment chemist devising a large-scale synthesis
Section B- Drug targets B1 ENZYMES Key Notes Enzymes Enzymes are proteins that catalyze the body s chemical reactions. The starting material for an enzyme-catalyzed reaction is known as a Active site The active site is a hollow or cleft on the enzyme surface where the substrate binds and the reaction takes place. The substrate is bound to the active site by intermolecular interactions. The active site contains amino acid residues, which act as nucleophiles or acid/ base catalysts in the reaction mechanism Mechanisms of Serine and cysteine can act as nucleophiles in a reaction mechanism, catalysis while histidine can act as an acid/base catalyst Substrate binding weakens important bonds and constrains the substrate in a specific nformation such that it will undergo reaction Enuyme inhibitors Competitive inhibitors compete with the naturai substrate for the active site. Noncompetitive inhibitors bind to allosteric binding sites and distort he active site so that it can no longer bind the natural substrate Reversible inhibitors bind by noncovalent interactions, whereas irreversible inhibitors are linked to the enzyme through covalent bonds Enayme selectivity Drugs should be as selective as possible for the target enzyme Related topics inding interactions( G2) Modeling studies(L4) Functional groups as binding The dawn of the antibacterial ag groups( G3) (1930-1945)(M4) Epidermal growth factor receptor L1) Enzymes are protein structures that act as the body s catalysts. a catalyst aids a chemical reaction by lowering the activation energy of the reaction. This speeds up the rate at which the reaction reaches equilibrium but does not affect the equilibrium itself. Therefore, an enzyme can catalyze a reaction in either direc- tion depending on the relative ratio of compounds present. The chemical that undergoes an enzyme-catalyzed reaction is known as a substrate. The substrate is bound to the enzyme to form an enzyme-substrate complex (ES), which then undergoes reaction to form the enzyme- bound product(EP)(Fig. 1).The product is then released and the enzyme is free to bind another substrate Since enzymes are proteins, they are made up of amino acid subunits linked together by peptide bonds. There are 20 essential amino acids in human biochemistry five of which are shown in Fig.2
Section B- Drug targets Fig. 2. Amino acids Active site The active site of an enzyme is usually a hollow or cleft on the protein surface into which the substrate can fit and bind (Fig 3). The substrate is usually bound to amino acids present in the binding site by a variety of interactions, such as hydrogen bonding, ionic bonding, van der Waals interactions or dipole-dipole interactions. For example, a substrate might bind to a serine residue by H bonding, to an aspartate residue by ionic binding and to a phenylalanine residue by van der Waals interactions. These binding interactions must be strong enough to hold the substrate long enough for the enzyme-catalyzed reac tion to take place, but weak enough to allow the product to depart once it is formed. This is important when it comes to designing inhibitors since one could introduce extra binding interactions such that the inhibitor 'sticks to the binding site and blocks it. substrat Active site./ Fig. 3. The active site
B1-Enzymes Substrate Product The active site also contains amino acids which assist in the reaction mecha- nism. Nucleophilic amino acids, such as serine or cystein ne are comn nvolved in enzyme-catalyzed mechanisms and will form a temporary covalent bond with the substrate as part of the reaction mechanism (Fig 4) The amino acid histidine is commonly involved as an acid /base catalyst. This is because the imidazole ring of the histidine residue can easily equilibrate between the ionized and nonionized forms, allowing the amino acid to act both as a source and as a'sink' for protons (Fig. 5). ionized Acts as an acid catalyst proton 'sink,) (proton source) Fig. 5. Histidine as an acid/base catalyst. MechanIsms of There are several reasons why enzymes catalyze reactions. We have alread catalysis mentioned that amino acids in the active site can aid the enzyme mechanism by Icting as nucleophiles or acid/base catalysts. Another reason why enzymes act as atalysts is the binding process itself. The active site is not the ideal shape for the substrate, and when binding takes place it changes shape in order to accommo- date the substrate and to maximize the bonding forces between the substrate and the active site. This is known as an induced fit (Fig. 6) However, these binding processes also mean that the substrate is forced to adopt a specific conformation (not necessarily the most stable conformation)in Induced fit
Section B- Drug targets order to bind effectively. Constraining the substrate into a specific conforma tion usually holds the molecule in the ideal position for further reaction with the cids. Another feature of the bind between substrate and enzyme is that important bonds in the substrate may be strained and weakened, allowing the reaction mechanism to proceed more easily. An example of an enzyme-catalyzed reaction is the hydrolysis of the this reaction, acetylcholine is bound in the active site such that it is held in posi tion for nucleophilic attack by a serine residue. a histidine residue is also posi- tioned ideally to act as an acid /base catalyst. Hydrogen bonding between the ester group of the acetylcholine and a tyrosine residue in the active site also serves to weaken the ester linkage, allowing it to be cleaved more easily. The mechanism shown in Fig 8 illustrates the roles played by serine and histidine H3C OH Ethanoic acid Enzyme Enzyme inhibitors are drugs that inhibit the catalytic activity of an enzyme inhibitors Inhibitors can be defined as being competitive or noncompetitive Competitive inhibitors compete with the natural substrate for the active site(Fig. 9). The CHa- ⊙0一 Nucleophile) (Acid catalyst) (Base catalyst) Fg. 8. Mechanism of hydrolysis by acetylcholinesterase (R=CH, CH RMe J