1. An Introduction to Drugs, Their Action and Discovery

1. 1. An Introduction to Drugs, Their Action and Discovery The basic concepts in Medicinal Chemistry Dr Seemal Jelani

2. Introduction Dr Seemal Jelani • Primary objective－ design and discovery of new compounds that are suitable for use as drugs • A team of workers－chemistry, biology, biochemistry, pharmacology, mathematics, medicine and computing, amongst others • Requires of drug discovery or design－ synthesis of the drug, a method of administration, the developmentoftests and procedures to establish how it operates in the body, and a safety assessment

3. Dr Seemal Jelani Drug discovery may also require fundamental research into the biological and chemical nature of the diseased state. Medicinal chemists need to have an outline knowledge of the above mentioned aspects.

4. 1.2 What are drugs and why do we need new ones? Dr Seemal Jelani Definition of drug －chemical substances that are used to prevent or cure diseases in humans, animals and plants Activity－ pharmaceutical/pharmacological effect on the subject, e.g. analgesic or β-blocker Potency－ the quantitative nature of the effect

5. Dr Seemal Jelani • The word “Drug” usually defined as agent used for the psychotic effect by the media or general public. • Even the drugs abused have their activity. • Drugs act by interfering with biological processes, so no drug is completely safe. • That is, suitable quantity to cure or excess to be poisonous! E.g. aspirin, paracetamol can be toxic if excesses.

6. Dr Seemal Jelani Side effect – unwanted effect usually; however, they are not always non-beneficial For example, the drowsiness side effect of anti-histamine may help sleep.

7. Dr Seemal Jelani Drug resistanceor tolerance (tachyphylaxis) occurs when a drug is no longer effective in controlling a medical condition. Reasons – induced oxidases in the liver that are able to metabolize the drug; a special enzyme induced to metabolize the drug; down regulated drug receptors

8. Therapeutic index Dr Seemal Jelani Chemotherapeutic index = Minimum curative dose /Maximum tolerated dose By Ehrlich in search of a safer antiprotozoal agent in 19th century -- more effective drugs showed a greater selectivity for the target microorganism than its host Therapeutic index = LD50/ED50

9. Evolution and revolution Dr Seemal Jelani Early 19th – plant extracts and pure isolates from medicinal plants appeared. Some of these drugs were very toxic Late 19th, to find less toxic medicines than those based on natural sources → synthetic substances as drugs Early 20th synthetics dominated the main origin of therapeutic drug origins

10. Dr Seemal Jelani Leads – the known pharmacologically active chemicals used in drug design and development Analogues – the-lead related compounds

11. Therapeutic index Dr Seemal Jelani • Paul Ehrlich and Sacachiro Hata who produced arsphenamine in 1910 – in the search of more effective anti-microbiotic agents: Atoxyl, Arsphenamine (Salvarsan)

12. Dr Seemal Jelani Structure–Activity Relationship (SAR) The structure–activity relationship (SAR) is the relationship between the chemical or 3D structure of a molecule and its biological activity

13. Dr Seemal Jelani

14. QSAR – quantitative structure–activity relationship Dr Seemal Jelani 1960s that Hansch and Fujita devised a method that successfully incorporated quantitativemeasurements into structure–activity relationship determinations This method was refined to build mathematical relationships between the chemical structure and the biological activity, known as quantitative structure-activity relationship (QSAR). .

15. Dr Seemal Jelani The most successful uses of QSAR has been in the development in the 1970s of the antiulcer agents cimetidine and ranitidine. Both SAR and QSAR are important parts of the foundations of medicinal chemistry

16. Concept of Drug Receptor Dr Seemal Jelani • In 1905 John Langley proposed that so-called receptive substances in the body could accept either a stimulating compound, which would cause a biological response, or a non-stimulating compound, which would prevent a biological response. • Receptor sites usually take the form of pockets, grooves or other cavities in the surface of certain proteins and glycoproteins in the living organism.

17. Dr Seemal Jelani Ligand Ligand is a small substance, that forms a complex with a biomolecule to serve a biological purpose It is a signal triggering molecule, bind to a site on a target (protein) The binding occurs by IMF, IB, HB, VWF

18. Myoglobin (blue) with its ligand Heme(orange) bound. Dr Seemal Jelani

19. Stereo electronic structure Dr Seemal Jelani Both molecular shape and electron distribution, is complementary with the stereoelectronicstructure of the receptor responsible for the desired biological action. The drug conformation adopted when binds to the receptor is known as active conformation.

20. Dr Seemal Jelani The section of the structure of a ligand that binds to a receptor is known as its Pharmacophore. E.g., the “quaternary nitrogens” that are believed to form the Pharmacophore of the neuromuscular blocking agent tubocrarine are separated in the molecule by a distance of 115.3 nm.

21. Dr Seemal Jelani Esters and N-substituted amides, for example, have structures with similar shapes and electron distributions but N-substituted amides hydrolyze more slowly than esters. However, changing a group or introducing a group may change the nature of the activity of the compound.

22. Membranes Dr Seemal Jelani Drugs normally have to cross non-polar lipid membrane barriers in order to reach their site of action As the polar nature of the drug increases it usually becomes more difficult for the compound to cross these barriers.

23. Modern Techniques Dr Seemal Jelani Computerized molecular modeling (1970s) – allows the researcher to predict the three-dimensional shapes of molecules and target, calculate the binding energy, and reduced the need to synthesize every analogue of a lead compound

24. Dr Seemal Jelani Combinatorial chemistry (1990s) – originated in the field of peptide chemistry but has now been expanded to cover other areas. Simultaneous production of large numbers of compounds, known as libraries, for biological testing. Used for structure–activity studies and to discover new lead compounds. The procedures may be automated.

25. 1.4 Leads and analogues: some desirable properties Dr Seemal Jelani • A molecular mass less than 500; • A calculated value of log P* less than 5; • Less than ten hydrogen bond acceptor groups (e.g. -O- and -N-, etc.); • Less than five hydrogen bond donor groups (e.g. NH and OH, etc.). • P = partition coefficient of octanol/water

26. Solubility Dr Seemal Jelani Any compounds that are potential drug candidates have to be soluble to some extent in both lipid and water. Ideal leads and/or analogues have a balance between their water solubility and their lipophilicity.

27. Structure Dr Seemal Jelani The nature of the structures of leads and analogues will determine their ability to bind to receptors and other target sites. Binding forces between a drug and a receptor – electrostatic bonds, such as hydrogen bonds and van der Waals’ forces, ion pair, and covalent bond

28. Dr Seemal Jelani A major consideration in the selection of leads and analogues is their stereochemistry. It is necessary to pharmacologically evaluate individual enantiomers as well as any racemates.

29. Stablility Dr Seemal Jelani Stability after administration and shelf-life Three strategies are commonly used for improving a drug’s in situ stability: Modifying its structure; prepare amore stable analogue with the same pharmacological activity Administering the drug as a more stable prodrug (A biologically inactive compound that can be metabolized in the body to produce a drug Using a suitable dosage form

30. Create a more stable analogue Dr Seemal Jelani

31. Dr Seemal Jelani Prodrug formation