1. An Introduction to Drugs, Their Action and Discovery The basic concepts in Medicinal Chemistry 2016/6/4Dr Seemal Jelani1

 Primary objective  Primary objective － design and discovery of new compounds that are suitable for use as drugs  A team of workers  A team of workers － chemistry, biology, biochemistry, pharmacology, mathematics, medicine and computing, amongst others  Requires of drug discovery or design  Requires of drug discovery or design － synthesis of the drug, a method of administration, the development of tests and procedures to establish how it operates in the body, and a safety assessment 2016/6/4Dr Seemal Jelani2 Introduction

 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. 2016/6/4Dr Seemal Jelani3

 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 2016/6/4Dr Seemal Jelani4 1.2 What are drugs and why do we need new ones ?

 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. 2016/6/4Dr Seemal Jelani5

 Side effect – unwanted effect usually; however, they are not always non-beneficial  For example, the drowsiness side effect of anti-histamine may help sleep. 2016/6/4Dr Seemal Jelani6

 Drug resistance or 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 2016/6/4Dr Seemal Jelani7

 Chemotherapeutic index = Minimum curative dose /Maximum tolerated dose  By Ehrlich in search of a safer antiprotozoal agent in 19 th century -- more effective drugs showed a greater selectivity for the target microorganism than its host  Therapeutic index = LD50/ED /6/4Dr Seemal Jelani8 Therapeutic index

 Early 19 th – plant extracts and pure isolates from medicinal plants appeared. Some of these drugs were very toxic  Late 19 th, to find less toxic medicines than those based on natural sources → synthetic substances as drugs  Early 20 th synthetics dominated the main origin of therapeutic drug origins 2016/6/4Dr Seemal Jelani9 Evolution and revolution

 Leads – the known pharmacologically active chemicals used in drug design and development  Analogues – the-lead related compounds 2016/6/4Dr Seemal Jelani10

 Paul Ehrlich and Sacachiro Hata who produced arsphenamine in 1910 – in the search of more effective anti-microbiotic agents: Atoxyl, Arsphenamine (Salvarsan) 2016/6/4Dr Seemal Jelani11 Therapeutic index

2016/6/4Dr Seemal Jelani12  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

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 1960s that Hansch and Fujita devised a method that successfully incorporated quantitative measurements 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). . 2016/6/4Dr Seemal Jelani14 QSAR – quantitative structure–activity relationship

 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 2016/6/4Dr Seemal Jelani15

 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. 2016/6/4Dr Seemal Jelani16 Concept of Drug Receptor

 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 2016/6/4Dr Seemal Jelani17

Myoglobin (blue) with its ligand Heme (orange) bound. 2016/6/4Dr Seemal Jelani18

 Both molecular shape and electron distribution, is complementary with the stereoelectronic structure of the receptor responsible for the desired biological action.  The drug conformation adopted when binds to the receptor is known as active conformation. Stereo electronic structure 2016/6/4Dr Seemal Jelani19

 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 nm. 2016/6/4Dr Seemal Jelani20

 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. 2016/6/4Dr Seemal Jelani21

 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. 2016/6/4Dr Seemal Jelani22 Membranes

 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 2016/6/4Dr Seemal Jelani23 Modern Techniques

 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. 2016/6/4Dr Seemal Jelani24

1.A molecular mass less than 500; 2.A calculated value of log P* less than 5; 3.Less than ten hydrogen bond acceptor groups (e.g. -O- and -N-, etc.); 4.Less than five hydrogen bond donor groups (e.g. NH and OH, etc.).  P = partition coefficient of octanol/water 2016/6/4Dr Seemal Jelani Leads and analogues: some desirable properties

 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. 2016/6/4Dr Seemal Jelani26 Solubility

 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 2016/6/4Dr Seemal Jelani27 Structure

 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. 2016/6/4Dr Seemal Jelani28

 Stability after administration and shelf-life  Three strategies are commonly used for improving a drug’s in situ stability: 1. Modifying its structure; prepare a more stable analogue with the same pharmacological activity 2. Administering the drug as a more stable prodrug ( A biologically inactive compound that can be metabolized in the body to produce a drug 3. Using a suitable dosage form 2016/6/4Dr Seemal Jelani29 Stablility

Create a more stable analogue 2016/6/4Dr Seemal Jelani30

Prodrug formation 2016/6/4Dr Seemal Jelani31