Chapter 1 An Historical Overview of Drug Discovery Ana Sofia Pina Abid Hussain and Ana Cec lia A Roque Summary Drug Discovery in modern times straddles three main periods The first notable period can be traced to the nineteenth century where the basis of drug discovery relied on the serendipity of the medicinal chemists The second period commenced around the early twentieth century when new drug structures were found which contributed for a new era of antibiotics discovery Based on these known structures and with the development of powerful new techniques such as molecular modelling combinatorial chemistry and automated high throughput screening rapid advances occurred in drug discovery towards the end of the century The period also was revolutionized by the emergence of recombinant DNA technology where it became possible to develop potential drugs target candidates With all the expansion of new technologies and the onset of the Omics revolution in the twenty first century the third period has kick started with an increase in biopharmaceutical drugs approved by FDA EMEA for therapeutic use Key words Drug discovery Proteomics Genomics High throughput screening Drug target Recombinant proteins 1 Introduction Drug research as we know it today began its career when chemistry had reached a degree of maturity that allowed its principles and methods to be applied to problems outside of chemistry itself and when pharmacology had become a welldefined scientific discipline in its own right J rgen Drews The alliance between Chemistry Biology and Pharmacology has enabled great improvements in Medicine over the last century 1 facilitating the design and discovery of new compounds which has always been the main goal in Medicinal Chemistry 2 These Ana Cec lia A Roque ed Ligand Macromolecular Interactions in Drug Discovery Methods and Protocols Methods in Molecular Biology vol 572 DOI 10 1007 978 1 60761 244 5 1 Humana Press a part of Springer Science Business Media LLC 2010 3 4 Pina Hussain and Roque compounds are designated as drugs because of their controlled use in the cure or prevention of disease Natural compounds isolated from natural sources such as plants micro organisms vertebrates and invertebrates 2 3 represent the major class of molecular drugs and these are involved in the treatment of 87 of all categorized human diseases 3 4 They were also the starting point for the discovery of important anticancer agents e g paclitaxel and camptothecin immunosuppressive agents e g cyclosporins and rapamycin and cholesterol lowering agents e g lovastatin and mevastatin 3 5 In the past serendipity played an important role in drug development and the creativity and intuition of the medicinal chemist was the basis for the drugs success 2 5 Since the drug discovery challenge is related to the identification and development of molecules that elicit a certain desired effect in a living organism proteins involved in key biological pathways represent potential drug targets 6 10 Therefore a study of the set of proteins expressed by a genome together with the development of high throughput methods has had a major impact in drug discovery 6 7 9 13 Nowadays drug research comprises several stages relying on expertise from a wide range of disciplines such as biology biochemistry pharmacology mathematics computing and molecular modelling The first stage includes combinatorial chemistry and high throughput screening in silico or in vitro for the selection of potential lead compounds 14 When a chemical structure shows activity and selectivity in a pharmacological or biochemically relevant screening protocol it can be considered as a potential hit compound 5 Ensuing steps are concerned with lead optimization and development selection At each stage an evaluation of the structure activity relationships SARs must be addressed 15 16 Drug like properties need to be studied in vivo through pharmacokinetics studies to evaluate the absorption distribution metabolism excretion ADME and interactions of a drug These studies ascertain physicochemical properties solubility permeability lipophilicity and stability in vitro and molecular properties molecular weight hydrogen bonding and polarity studied in silico or in vitro 5 15 17 Beyond this strategy defined pharmaceutical profiling a separate set of criteria correlating physical properties with oral bioavailability has been formulated by Lipinski et al and designated as the rule of five 4 15 18 This rule is associated with the solubility and permeability of a compound Specifically it states that when a compound possesses poor absorption or permeability there are 5 hydrogenbond donors the molecular mass is 500 calculated log P is 5 P partition coefficient the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium and the sum of nitrogen and oxygen atoms in a molecule 10 4 5 18 Once the drug has shown to An Historical Overview of Drug Discovery 5 be a good candidate clinical trials are required for its approved use by the Food and Drug Administration FDA in North America or the European Agency for the Evaluation of Medicinal Products EMEA in Europe 5 In these clinical trials the candidate drug is administrated to normal human volunteers for toleration Phase I then to patients having the condition that the drug has been designed to treat Phase II and finally to a large number of patients Phase III 2 5 Genomics and Proteomics have both contributed towards developments in the drug discovery process by facilitating the cloning expression identification and study of target proteins for specific diseases 19 Typical proteomics technologies as 2 D electrophoresis combined with mass spectroscopy MS and high performance liquid chromatography HPLC coupled with MS HPLC MS provide good separation of proteins 6 9 20 Increasingly affinity chromatography and micro array technologies have emerged as powerful techniques for probing drug protein interaction In the former case the elucidation of drug protein interaction involves direct interrogation of the substrates through covalent binding between protein and drug candidates immobilized into a suitable solid support 11 In the latter the monitoring of the binding of a small molecule to a wide range of proteins can be performed rapidly and simultaneously 7 X ray diffraction and nuclear magnetic resonance NMR are also important techniques for the prediction of the 3D structure of an
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