Chapter 1An Historical Overview of Drug Discovery1. IntroductionReferencesChapter 1An Historical Overview of Drug DiscoveryAna Sofia Pina, Abid Hussain, and Ana Cecília A. RoqueSummaryDrug 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“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 well-defined scientific discipline in its own right”.Jürgen DrewsThe 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 1. IntroductionAna Cecília 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 201034 Pina, Hussain, and Roquecompounds 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, seren-dipity 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, bio-chemistry, 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 opti-mization 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 permea-bility of a compound. Specifically it states that when a compound possesses poor absorption or permeability, there are >5 hydrogen-bond 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 toAn Historical Overview of Drug Discovery 5be 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 devel-opments 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 electro-phoresis combined with mass spectroscopy (MS) and high perform-ance 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
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