Lecture 3

1. Lecture 3 Finding a lead compound Dr. Abd El Raheim Donia

2. Finding a lead compound • Once a target and a testing system have been chosen, the next stage is to find a lead compound. • A lead compound is a compound which shows the desired pharmaceutical activity. * The lead compound provides a start for the drug design and development process. Dr. Abd El Raheim Donia

3. There are various ways in which a lead compound might be discovered. • 1- Screening of natural products (the plant kingdom, the microbial world, the marine world, animal sources, venoms and toxins). • Natural products are a rich source of biologically active compounds. • Many of today’s medicines are either obtained directly from a natural source or were developed from a lead compound originally obtained from a natural source. • Most biologically active natural products are secondary metabolites with quite complex structures. This has advantage in that they are extremely novel compounds. Dr. Abd El Raheim Donia

4. 2-Medical folklore. • 3-Screening synthetic compound “ libraries”. • 4-Existing drugs (Me too drugs & Enhancing the side effects). Many companies use established drugs from their competitors as a lead compound in order to design a drug. By modifying the structure in such way that avoids the patent restrictions, retain the activity, and improved the therapeutic properties. For example: Captopril (Anti-hypertension) used as lead compound by different companies to produce their own anti-hypertension drugs. Dr. Abd El Raheim Donia

5. 5-Starting from natural ligand or modulator (natural ligands for receptors, natural substrates for enzymes, enzyme products as lead compounds, natural modulators as lead compounds). E.g. Adrenaline and noradrenaline (natural neurotransmitters) were used for development adrenergic β-agonists such as Salbutamol, dobutamine, xamoterol, H2 antagonists as cimetidine, and morphine (led to opiate receptors, and endogenous opiates : endorphins and enkephalins. Dr. Abd El Raheim Donia

6. 6-Combinatorial synthesis. • 7-Computer aided design. • 8-Serendipity and prepared mind. • 9-Computerized searching of structural databases. • 10-Designing lead compounds by NMR. Dr. Abd El Raheim Donia

7. Disciplines in Drug Discovery A. Chemistry: The first step after identification of the target in any drug discovery process is the decision of which natural compounds or chemical structures to synthesize. There are various means by which compounds can be isolated or synthesized for biological activity testing. Dr. Abd El Raheim Donia

8. B. Pharmacology: After chemistry step, NCE is tested against a single or multiple therapeutic targets to determine if the NCE has any potential to elicit a pharmacological response. This pharmacological testing can be done in multiple different ways depending on the number of compounds to be screened, the speed at which you need to screen, the limitations of what is known about a biological target, or the reagents available to the researcher. Dr. Abd El Raheim Donia

9. C. ADME Properties: The properties of absorption, distribution, metabolism, and elimination (ADME) of potential new drugs are the disciplines of pharmacokinetics, pharmaceutics, drug metabolism, and drug transport. Dr. Abd El Raheim Donia

10. D. Pharmacogenomics: Pharmacogenomics (pharmacogenetics) is the grouping of a pharmacological drug response from a population based on the genetic variation of that population. In some instances, different individuals in a population respond to the same drug in different ways; these variations can be due to genetic variations in the biological target (receptor), genetic differences in drug transport, or the metabolizing enzymes that are involved in drug absorption and clearance. E. Toxicology: In addition to the above-mentioned properties, the potential toxicological aspects of discovery compounds should be evaluated at the earliest opportunity. Dr. Abd El Raheim Donia

11. Drug Discovery from Nature • The Impact of Natural products on Drug Discovery: Dr. Abd El Raheim Donia

12. A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design. Dr. Abd El Raheim Donia

13. Natural products may be extracted from: * Tissue of terrestrial plants. * Marine organisms. * Microorganism fermentation broths. A crude (untreated) extract from any one of these sources typically contains novel, structurally diverse chemical compounds. Chemical diversity in nature is based on biological and geographical diversity, so researchers travel around the world obtaining samples to analyze and evaluate in drug discovery screens or bioassays. This effort to search for natural products is known as bio prospecting. Dr. Abd El Raheim Donia

14. Natural products have provided the inspiration for most ofthe active ingredients in medicines: around 80% of medicinalproducts up to 1996 were either directly derivedfrom naturally occurring compounds or were inspired by anatural product, and more recent analysis confirms thecontinuing importance of natural products for drug discovery. Dr. Abd El Raheim Donia

15. Plants have formed the basis of sophisticated traditional medicine systems that have been in existence for thousands of years, and their uses by many cultures have been extensively documented. These plant-based systems continue to play an essential role in healthcare, and it has been estimated by the World Health Organization that approximately 80% of the world’s inhabitants rely mainly on traditional medicines for their primary health care. Dr. Abd El Raheim Donia

16. Drugs derived from natural products launched in Europe, Japan and the United States 2001–2005. Cited from Kin S. Lam (2007).New aspects of natural products in drug discovery.TRENDS in Microbiology Vol.15 No.6. 279-289. Dr. Abd El Raheim Donia

17. Natural products can be obtained from different sources such as: 1-The plant kingdom: It is rich source of lead compounds (e.g. morphine, cocaine, quinine, tubocurarine, nicotine and muscarine, paclitaxel (Taxol, anticancer), either useful drugs as morphine or basis for synthetic).Plants continue to remain a promising source of new drugs. 2-The microbial world: microorganisms such as bacteria and fungi are richfor lead compounds (e.g.pencillins, cephalosporines, tetracyclines, aminoglycosides, chloramphenicol, rifamycins). Dr. Abd El Raheim Donia

18. 3-The marine world: coral, sponges, fish and marine microorganisms havebiological potent chemicals, with interesting, anti-inflammatory, antiviral, and anticancer activity. E.gCuracin A (anti-tumour, from marine cyanobacterium). 4-Animal sources: antibiotic peptides were extracted from the skin ofAfrican clawed frog. Epibatidine (potent Analgasic) was also obtained from Ecuadorian frog. Dr. Abd El Raheim Donia

19. * Combinatorial chemistry: The use of a small set of chemical building blocks, combined together in multiple ways using standard chemistries, to create large libraries of compounds that may be screened for potential new drugs. * Genomics: Establishes the relationship between gene activity andparticular diseases. Dr. Abd El Raheim Donia

20. 1- Cutler, Stephen J.; Cutler, Horace G. (2000). Biologically active natural products: pharmaceuticals. CRC Press. p. 5. ISBN9780849318870.2- Newman DJ, Cragg GM Natural products as sources of new drugs over the last 25 years. Journal of Natural Products 70, 461-477 (2007).3- Dan Bensky, Steven Clavey, Erich Stoger, and Andrew Gamble Chinese Herbal Medicine: MateriaMedica, Third Edition2004 Dr. Abd El Raheim Donia