Introduction to Drug Design & Drug Discovery PDF

By: Dr./ Mohamed Abdel-Aal 1  Introduction Medicinal chemistry  A chemistry-based discipline, involving aspects of biological, medical and pharmaceutical sciences.  It is concerned with discovery, design, identification and prepar...

By: Dr./ Mohamed Abdel-Aal 1  Introduction Medicinal chemistry  A chemistry-based discipline, involving aspects of biological, medical and pharmaceutical sciences.  It is concerned with discovery, design, identification and preparation of biologically active compounds, studying their mode of action at the molecular level, building up of structure activity relation ships and studying of their biotransformation.  In pharmaceutical industry, medicinal chemistry deals with the design and synthesis of new compounds for biological evaluation as potential new drugs. The medicinal chemist  A competent organic chemist, with good knowledge in biological science.  Attempts to design and synthesize new pharmaceutical agents with desired biological effects on the human body or some other living systems, these agents serve as lead compounds for development of new drugs. Discovery and development of new agents is a complex process involves large number of talent people from different fields including chemistry, biochemistry, physiology, pharmacology, pharmaceutics and medicine, where medicinal chemistry is concerned mainly with organic, analytical and biological aspects. Thus medicinal chemistry has a strategic position between the chemistry and biology.  Fields of Study in Medicinal Chemistry Invention, discovery, design, identification and preparation of biologically active agents Studying the metabolism of drugs Interpretation of the mechanism of action of drugs Construction of structure-activity relationships Prediction of the biological activity of compounds from their physicochemical parameters Course objectives: 1. To predict the biological response, if any, from a chemical structure of compounds. 2. To relate the structural features to the physicochemical properties. 3. Predicting the biochemical mechanism of action of a biologically active compound from its chemical structure. 4. To suggest suitable analytical methodology. 5. Be able to use enzyme or receptor models to relate chemical structure to biological activity. 6. Be able to predict the biological response resulting from chemical alteration of a biochemical pathway. 3  Drug:  A bioactive substance, which is a component of a medicament that acts to affect some body functions so as to relief, cure or prevent diseases.  The effects of drugs represent the final result of complex processes and interactions with biological systems of the body.  A given drug has three main phases; 1. Pharmaceutical phase: Represents liberation of the drug from a dosage pharmaceutical form. 2. Pharmacokinetic phase: Includes the absorption, partitioning, biotransformation and excretion processes (ADME). 3. Pharmacodynamics: The interaction of the drug and its metabolites with specific binding sites. 4 Drug sources: Drugs can be obtained from different sources including natural, semisynthetic, synthetic and other sources. 1. Natural sources Drugs from natural origin come from three sources; a. Mineral sources (9.1%) Many inorganic substances are used as medicine or inter in medicine components. For example Sod. bicarbonate antacid and ferrous salt in treatment of anemia. b. Animal sources (8.7%) Drugs from animal sources include some hormones (such as insulin) and vitamins (vitamins A, E from fish liver oils). c. Plant sources (11.1%) Most of natural compounds are from plant origin, examples include alkaloids, cardiac glycoside, antibiotics and anticancer drugs. 2. Synthetic sources (48.9%) The majority of drugs used today are synthetic compounds, the development in organic, organometallic as well as the regioselective and sterioselective catalysts lead to great advances in total synthesis of natural products. Synthetic drugs replace the natural compounds, and provide an improved, simplified synthetic analogues. Also, the production of synthetic drugs doesn’t depend on unpredictable botanical sources. 3. Semisynthetic sources (9.5%) Drugs of this group represent an intermediate position between natural and synthetic agent. They include various fermentation products such as antibiotics, amino acids and vitamins. 4. Other sources (12.7%) Include microbial drugs (antibiotics), sera and vaccines. Recently bacteria are included in production of complex natural compounds. For example, the production of insulin by the genetic engineering, this technology is called “recombinant DNA technology” and involves the transfer of gene responsible for production of insulin into bacteria, so this gene translation expressed production of insulin. Nomenclature Of Drugs: Chemical name: (Acetylsalcylic acid) Code designation: (SC-40230); (AZT, Azidothymdine) Non-propriety name (Generic name): (Aspirin) Trade name: (Aspocid, Rivo) Drug classification Drugs can be classified according to many aspects as following; a. Pharmacological effect: Analgesics, antihypertensives, sedatives and hepnotics, antianginal ……etc b. Chemical structures: Quinolones, barbiturates, steroids, NSAID, pencillines …. etc c. Target system: Antihistamines, cholinergics, adrerengics …… etc. d. Site of action (receptors): Anticholinesterase (enzyme inhibitors). Drug discovery The lead compounds (well established chemical substances with biological activity) may be obtained by; 1. Serendipity It refers to accidental discovery of a new drug, or the novel uses of known drugs in laboratories or clinic by physicians, pharmacists or other investigators. E.g., Observation of antibacterial action of penicillin by Fleming (1929) in a culture of bacteria that contaminated by fungus. 2. Natural sources The active principles isolated from plants and their derivatives, represent the most important source for new drugs. Examples include, the isolation of morphine, ephedrine, atropine and many others. Most of these compounds act by interaction with certain receptors or enzymes and thus they are useful as lead structures for drug discovery. 3. Random screening In this method, all available chemical compounds are subjected to variety of biological tests, hoping that some compounds may show useful activity. This method for finding new drugs is not very useful. Using this approach for discovery of a new anticonvulsant, it might be necessary to screen half a million of chemical compounds. 4. Drug design methods Rational approach to drug design has became the main route for new drug discovery. To use this approach, the etiology of a given disease or at least the disturbed biochemical process should be known. Examples for this approach includes the discovery of the angiotensin-converting enzyme inhibitors (ACEIs). Drug discovery process Investigational new drugs Target identification and characterization: Identifying the function of a possible therapeutic target (gene/protein) and its role in the disease. Target validation: The application of a range of techniques that aim to demonstrate that drug effects on the target can provide a therapeutic benefit with an acceptable safety profile. Virtual screening: A set of computational methods that analyzes large databases or collections of compounds in order to identify potential hit candidates. Assay development: Creating test systems (assays) to evaluate the effects of chemical compounds on cellular, molecular or biochemical processes of interest. HTS (high-throughput screening): Assays enable the testing of large numbers of chemical substances for activity in diverse areas of biology. Hit to lead (lead generation): it is a stage in early drug discovery where small molecule hits from a high throughput screen or other programs are evaluated and undergo a limited optimization to identify promising lead compounds. Steps for drug approval Natural compounds or from synthetic program In vitro evaluation of activity and enzyme/receptor assay Active Animal tissue models Experimental pharmacokinetics Active In vivo animals testing for activity and toxicity Phases I-III human Approval Phase IV (NDA)  Drug targets and mechanism of drug action The knowledge about the site (target) of drug action and the study of mechanism by which the drug exert its biological effect helps greatly in development of more safe and more potent new drugs. Biological activity of drugs my be due to interaction with one of the following targets. a. Enzymes In this case, the drug acts by reversible or irreversible inhibition of the target enzyme. b. Receptors Drugs bind to receptors and produce agonistic or antagonistic action. c. Ion channels Drug acts by blocking or opening of channel. d. Transporters Drug acts by inhibition of an endogenous active substance uptake. e. DNA Drugs may act by interaction with DNA structure by alkylation, binding to minor groove and/or intercalation, these modifications in DNA structure results in formation of wrong substrates. Some definitions Ligand Any molecule that binds to a biological macromolecule. Enzyme An endogenous biocatalyst that helps conversion of substrate/s to product/s. Substrate A molecule on which the enzyme acts to form a product Inhibitor Ligand that prevent the binding of a substrate to its enzyme, either in a direct (competitive) or indirect (allosteric) manner, reversibly or irreversibly. Receptor A membrane-bound or soluble protein or protein complex, which exerts a physiological effect (intrinsic effect), after binding with an agonist, via several steps. Agonist A receptor ligand that mediates a receptor response (intrinsic effect). Antagonist A receptor ligand, which prevents the action of an agonist, in a direct (competitive) or indirect (allosteric) manner. Partial agonist A high affinity antagonist, which itself has more or less pronounced intrinsic activity. Drug-Receptor Interaction Drug molecule interacts with a specific molecule in the biologic system that plays a regulatory role. This molecule is called “target molecule”, and the site on the macromolecules that the drug binds with is called “binding sit”. The site for drug action may also be defined as a “receptor”. Drug Targets: Receptors Consist of proteins imbedded in cell membranes. Some are isolated and identified e.g. GABA, GH, adrenergic & muscarinic. Most of them are difficult to be isolated and to determine their structures Enzyme & DNA Most of them are isolated and identified Difference between enzymes and other receptors interaction E + S E-S E + P R + D R-D Transduction events R-D complex is reversible E-S is irreversible Signal Transduction (ST) It is a process by which receptor activation results in modification of cellular structure and function. This occur with the receptors on the external surface of the cell membrane (G protein coupled receptors). Three events take place when the ligand meets the receptor: 1. The receptor recognize the ligand and fitting or binding takes place. 2. Thermodynamics of binding is transformed to transducing element, resulting in changing either enzyme activity or channel gating. 3. Altered level of intracellular second messenger Thus a brief activation of small number of receptors may result in a magnified response by the cell. Amplification can also occur via molecular cascade, where one initial signal can trigger a multitude of intercellular reactions which lead to an enhanced cellular response  Receptor Molecular Cascade Initial signal  Drug Classification A) Specific drugs 1. They exert their effect at site of action at very low concentrations, from nano-to micromolar 2. Mostly they are tissue selective 3. Small structural modification may has serious effects on its activity 4. Some structural modification may change the compound from an agonist to antagonist NH NH S H2N N H3CHN N N H Histamine Burimamide Compound Intestine Heart muscles 3 NH (Ileum) (Atrium) 4 Histamine 100% 100% 2 1-Methyl