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Drug Discovery Presentation
- 1. Drug discovery and design Lewis Hudspith Holly Laurence Lucy Hague Karmjit Grewal Matt Franklin
- 2. From natural sources Notable accidental discoveries -LSD; Powerful psychedelic with potential for treatment of mental issues. -Penicillin; a very diverse group of antibiotics. Modified compounds from nature -Morphine and other opioids; derived from thebaine within poppies. -Ibuprofen; derived from propanoic acid. Methods of detection and extraction -Similar chemical structures. -Observation within nature.
- 3. Rational Drug Design What is Rational Drug Design? 1. Structure Based Drug Design 2. Ligand Based Drug Design 1. Structure based drug design a. Determine 3D structure of the biological target b. Biological targets are mainly proteins c. Virtual Screening d. Molecular Docking e. Aim - “to achieve optimized conformation for both receptor and ligand and the relative orientation between protein and ligand such that the free energy of overall system is minimized.” (Mukesh and Rakesh, 2011) f. Ligand docked onto the protein and a score is generated g. High affinity ligand binding increases the potency of a drug h. Potency is a measure of strength and is the “amount of drug required to produce an effect of a given intensity, so if 5 milligrams of drug A produces same effect as 10 milligrams of drug B. Drug A is twice as potent” (Moroney, 2014) i. Next process is optimization
- 4. High-Throughput Screening of Small Molecules • What is HTS? • Target finding and early drug discovery • How it works • The future - vHTS (Ng, 2009)
- 5. Virtual High-Throughput Screening (vHTS) (Subramaniam et al., 2008)(Sliwoski et al., 2014)
- 6. Absolute Configuration X-Ray Crystallography • Most reliable method • At least 1 heavy atom req • Very slow technique Vibrational Circular Dichroism • One of two forms of VOA • Good for analysing small molecules (in solution) • Only a small sample req • Far more rapid than X-ray Checking for Chirality (He, no date)
- 7. To conclude In the future...
- 8. References • HE, Y. (no date) Chiral Analysis in Drug Discovery and Development. Discovery Technology. • MUKESH, B. and RAKESH, K. (2011) Molecular Docking: A Review. vol. 2., International Journal of Research in Ayurveda and Pharmacy. • MORONEY, A.C. (2014) Drug Action. [online] Last updated April. http://www.merckmanuals.com/home/drugs/drug_dynamics/drug_act ion.html • NG, R. (2009) Drugs: From Discovery to Approval. 2nd ed, Wiley- Blackwell. • SLIWOSKI,G; KOTHIWALE, S; MEILER, J. and LOWE, E. Jr. (2014) Computational Methods in Drug Discovery. Pharmacological Reviews. • SUBRAMANIAM, S., MEHROTRA, M. and GUPTA, D. (2008) Virtual high throughput screening (vHTS) – A Perspective. Biomedical Informatics Publishing Group.
Editor's Notes
- We have been looking at methods of drug discovery and their application in to modern science. Natural resources Lewis High throughput screening of small molecules Karmjit Rational drug design Holly Virtual high throughput screening Lucy Analysing chirality in candidate drugs Matt
- Lewis LSD discovered from fungus ergot, albert hoffman researching derivatives of lysergic acid with intensions of discovering a respiratory system stimulant. Penicillin discovered by Alexander Fleming when a petri dish containing staphylococcus was left exposed to open air, Penicillium mould contaminated it and destroyed the staphy.. Opium poppy contains many opiate alkoids which can be synthesized into potent painkillers such as oxycodone and other things like heroin… Ibuprofen derived from propanoic acid is a very common and useful anti-inflammatory. From Propanoic acid which is found in most life forms in fatty acids. Also is a biproduct of degradation of sugar. Scientists can predict the effect of compounds based on their structure, similar compounds can have similar uses. Studying unique properties of organisms can lead us to determining any unique and potentially useful compounds they contain. E.g. Halaven, found in sea sponges is a potent anti-cancer drug. To improve stability a ester bond within the compound is replaced with a ketone group. This also improves the potency of the compound. *link to previous point* It was discovered by observing the way sea sponge’s cells replicate under certain conditions.
- holly
- Karmjit Hello, today I will be speaking to you about high throughput screening of small molecules also known as hts. Hts is a modern screening process used in the discovery of new drugs. It is a automated robotics system, a machine, that runs many different tests on molecules and screens them to see if they are potential new drugs. The samples that are screened are obtained from researchers around the world. The aim of HTS is to see if a sample molecule can react with the active site on a protein or enzyme. If the sample can interact with the active site then a signal is given off, this signal, usually a fluorescent signal, is then detected. If a sample has many signals detected then it can be studied further to see if it is a potential new drug. The samples are put in to wells on a plate, these wells are tiny they are nanolitre size. This is useful as you don't need a lot of your sample, as samples can be hard to get or expensive. Depending on the HTS system there can be a different amount of wells usually the more wells there are the more tests can be run in a shorter time making it more efficient. Usually there are either 96 wells or 384 wells but more newer systems have 1536 wells these are known as ultra high throughput screening and they can test up to 100,000 samples a day. This is a well used system in the pharmaceutical industry especially as many new drugs are needed and samples are being discoverd and need to be screened quickly. It is a mainly automated system and it is accurate and cost effective as you have robots doing a lot of the work. The future of this technology lies in more computational drug discovery such as virtual high throughput screening.
- Lucy Virtual HTS is a computational method of drug design. It combines virtual screening and HTS to accelerate the drug discovery process. Virtual screening searches compound databases for compounds with the desired structure and properties needed to fit the target receptor site. It contributes to the high success rate of screening experiments. HTS is one method of these screening experiments, it can perform millions of assays but consumes a lot of time and money. Combining the methods makes the process cheaper and more efficient as more assays have the desired effect.
- Matt It’s important for companies to investigate drug chirality because in the current pharmaceutical climate, around two thirds of the drugs on the global market are chiral. It’s crucial to know the exact structure of these chiral drug compounds as one isomer could be the one responsible for the beneficial effects, whilst the other could be inactive, or even potentially harmful, like in the famous case of the drug thalidomide. Since the early ‘90s, the pharmaceutical industry has been required by law to give full details of any chirality in the drugs that they develop. To do this, they need to analyse something called the absolute configuration of the potential drug. An AC is described as the 3D arrangement of the atoms in a chiral molecule. Two of the ways companies can do this are shown on the board. X-ray crystallography is considered the most reliable method for determining the AC of a molecule, and involves growing a crystalline structure and then shining a beam of x-rays onto it to build up a 3D picture of the sample structure. However, it has several draw backs. For a start, it requires there to be at least one atom in the molecule to have an atomic weight greater than 23, and a single, pure crystal of the drug must be made first. In addition to that, the technique is very slow and often by the time the results get back to the chemist in the lab, other tests have already shown that the candidate drug is of very little interest. For this reason, the technique is often used at the late discovery or early development stages only. By contrast, the technique of VCD provides a far more rapid and quick analysis of the chiral structure, by examining the vibration of its bond when placed in an induced-polarised environment. A very small amount of sample is required (usually 5 to 10mg) as it doesn’t need to be tested multiple times. It’s also really good for analysing small molecules that may be unsuitable for use in other methods, and is useful right from the early drug discovery stage. In industry, both techniques are used in combination with others to investigate the AC of the candidate drug, allowing the pharmaceutical companies to go on to check the safety of it and also the financial worthwhile of investing any more money into its development.
- Individually these techniques are effective, but in reality a combination of all of them, and more, is employed to discover, design and develop new drugs. Although with an increasing demand for new medicines and ever more powerful drugs, more techniques may need to be developed in order to keep up with the changing demands of the market.