Growing knowledge of cell biology at the fundamental molecular level opened the door to new ways of inventing drugs

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1 E-tutorial 5 Rational drug design - The way we find new medicines was modernised as the 20 th and 21 st centuries progressed - Modernisation was driven by many factors, but above all by an improved understanding of biological mechanisms - With a better knowledge of what goes wrong in diseased tissues, we can better design drugs that help restore normal functions Growing knowledge of cell biology at the fundamental molecular level opened the door to new ways of inventing drugs As Protein targets or receptors were defined, it became possible to design drugs that bind specifically to them - Key: A rationally designed drug is intended to act specifically with a particular protein target or receptor - Lock: Drug binding site on a receptor protein. Not all proteins contain such sites. These are said to be druggable - Knob: is analogous to the protein target. Just as a knob allows it to be opn otherwise closed, a target protein is essential for some cellular functions Main steps in rational drug design strategies Disease focus We choose a human disease for which new drugs are needed: as it is expensive process it is handy to focus on diseases that do not have remedies evaluable. Target Selection We then identify a protein target or potential drug receptor that plays a clear role in the onset or progression of the disease of interest. Drug receptor usually a protein Receptor analysis A technique called x-ray crystallography is used to determine the fine structure of the receptor o interest

2 Virtual model X-ray diffraction data is analysed using computer software to construct a realistic and detailed molecular structure of the receptor. Virtual model of receptor (incudes potential drug-binding site) Drug design Once the geometry of the protein is understood medicinal chemists may design molecules that bind to critical sites. Such molecules can be prototype drugs for further testing Drugs interact with receptors in at least 3 ways 1. Ionic bonds: are electrostatic and occur between oppositely charged drug is attracted to a negative charge on a protein. For example, a glutamate residue, or vice versa 2. Van der Waals bond: these bonds are weak in terms of individual atoms, but many interactions within an entire molecule can be significant. They are due to fluctuations in electron clouds around atoms 3. Hydrogen bonding: these relatively weak interactions occur between hydrogen and nitrogen or oxygen atoms. These can be in either the drug or the receptor. These bonds act over short distances Such technologies as x-ray crystallography and NMR imaging can map the terrain of drugbinding sites in receptors Surface of drug receptor is analysised by process above They find pockets and crevices in drug binding domains Then they can locate possible drug bonding sites (e.g. positive and negative charged sites) Drug is designed to selectively dock with receptor In today s world, much of the rational design and testing of molecules occurs in a virtual environment like computers

3 Modern Pharmacology contributions Paul Earling Salvarsan - John Langley Professor of Physiology Cambridge University UK - Pioneered study of the pharmacology of nicotine - Introduced idea of receptive substances - Bird muscles: adminster the drug into the gastrocnemius muscle contraction bends bird leg - Nicotine was administered - Comprised of muscle fibres, bundles of myofibrils Neuromuscular junction - Synaptic clef - Neurotransmitter = acetylcholine - Stored in packets or vesicles - Receptor exists in open or closed form - Nerve impulse triggers neurotransmitters release into the cleft - Binding of neurotransmitter opens receptor channel - Flow of sodium and potassium ions through channel triggers muscle contraction Big idea - Attack the same type of receptors - receptive substance or receptors Aj Clarke, JH gaddum Maths based methods for studying interactions of drugs with their receptors Organic chemistry Starting molecule that binds to drug receptor but not as strongly This might be as the receptor contains an underutilized pocket near the drug binding site Chemists make many related molecules for testing as new drugs Tester molecules contain groups that may allow binding to pocket Total synthesis - seeks to build complex molecules from simple chemicals - goal is to achieve desired molecules in as few steps as possible - try to make as much product as possible ( high yield - Robert woodward was early pioneer nobel

4 Organ chemistry provides sets of molecules for drug testing libraries Asses binding strength screening Rulenza Influenza the scourge of humanity Highly contagious infection caused by airborne flu virus High potential for emergence of new pandemic-causing strains e.g. bird flu, swine flue Transmitted by coughing, sneezing, touching mouth etc. More serious symptoms than common cold e.g. fever, chills, muscle aches, sore throat Major global pandemics in , , Flu viruses in a nutshell - Flu viruses belong to the orthomyoxoviridae family of airborne viruses - Single stranded RNA genome - Three subtypes; A, B and C each of which continually produce variants - Only A and B types cause disease in humans Glycoproteins and infection - The viral envelope contains spike-like projections made of glycoproteins ie proteins tagged with sugar molecules - These promote virus attachment to cells - They act like tiny patches of Velcro, allowing infection of cells in the respiratory tract Neuraminidase is a vital envelope glycoprotein which chews up mucous helping viruses penetrate the respiratory tract More importantly it helps newly made viruses escape from infected cells X-ray structural insights - In the 1980 s, Australian researchers crystallised flu virus neruamidinase - The identified a slot within the protein which binds the substrate for the neuraminidase enzyme - This knowledge stimulated an intense search for inhibitor drugs Zanamivir

5 - Using rational design ideas, Australian researchers led by mark von itzstein invented zanamivir - This drug binds to the slot in flu neuraminidase and prevents it helping new viruses depart infected cells - Zanamivir is used to treat influenza a and b infections The Relenza story - Zanamivir was licensed to glaxosmithkline who marketed it in inhalable form as Relenza - It faced competition from another neuraminidase inhibitor, Tamiflu - Relenza shortens flu symptoms by a day or two, and helps prevent new infections during outbreaks Issues to approach A good target It is absolutely essential that chosen protein target plays an important role in the disease of concern. Otherwise a great deal of effort can be wasted. A stable target Problems can arise if the target changes during a course of a disease or epidemic. This can be a problem with cancer drugs as well as flu medicines. E.g. the target acquires mutations to evade drugs Doesn t work in the body While rationally designed drug might bind well to its target in a test tube, it can fail to work in the human body for any number of reasons. E.g too toxic, falls apart in acidic stomach contents etc.