Drug discovery

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Chapter: Pharmaceutical Drugs and Dosage: Drug discovery

Throughout history, new drug discovery has enabled human well-being and advancement, not only by ensuring survival in the wake of infections and debilitating diseases but also by steadily advancing the quality of life.

Drug discovery


Throughout history, new drug discovery has enabled human well-being and advancement, not only by ensuring survival in the wake of infections and debilitating diseases but also by steadily advancing the quality of life. For example, the discovery of penicillin by Alexander Fleming in 1928 saved countless lives and paved the way for the antibiotic medicines. More recent examples of life-saving medicines include the discovery and commercializa-tion of statins for the management of hypercholesterolemia and humanized monoclonal antibodies targeting the immune checkpoints for the immuno-therapy of cancer. Prominent examples among the quality-of-life improving therapeutics are the drugs for the management of pain, hypertension, gas-trointestinal disorders, and countless others. New drug discovery remains a continuing priority and exhibits relentless effort of governments, private corporations, and academia alike. This chapter will outline contemporary practices in new drug discovery and development, with an emphasis on the interdisciplinary process, stage-gate paradigm, and the key features that ensure safety and efficacy of every new drug through the earliest stages of drug discovery by commercialization.

Elements of drug discovery

Early discovery starts with the identification of disease area and molecular targets that may be useful in the clinical setting to modulate a particular disease condition. Several drug candidates that may be able to produce the desired outcome at the chosen drug targets are produced. The activity of these candidates is assessed in in vitro assays, and candidates presenting high efficacy are shortlisted. Structure–activity relationships (SARs) are developed to help narrow down the drug candidates to the ones with the greatest potential for efficacy at the lowest dose.

Early discovery is involved not only in the generation of drug can-didates but also in the assessment of their activity and toxicity in cell culture–based, in vitro, and in vivo systems (animal species). These often require development of disease models on which compounds can be tested. Assessment of relative activity and potential of different com-pounds must be made under a multitude of criteria, thus requiring an effort to optimize the relative performance of a compound in several attributes that are important for success in the overall discovery and development process.

Typical drug discovery and development process (Figure 1.1) involves a series of iterative work streams that develop and mature in parallel. Target selection and validation often precede first discovery efforts and continue to develop concurrently with the discovery drug candidate screening. Target screening and validation involve the following steps:

Figure 1.1 Key activities involved in drug discovery and development research.

·           Understanding disease pathophysiology and underlying cellular or subcellular mechanisms.

·           Target engagement–effect studies in cell culture or in vitro systems, with a view to develop a high-throughput assay that can be used for the screening of new drug candidates.

·           Efficacy, toxicity, and preliminary pharmacokinetic studies in ani-mals relevant to disease pathophysiology and candidate drugs. These studies may involve the use of transgenic animals that exhibit the dis-ease or modulation of particular biochemical processes and the use of antisense oligonucelotides or RNA-silencing approaches to modulate subcellular genetic pathways.

Discovery of new drug candidates relies on target screening and validation efforts to not only identify the right target but also provide a high-throughput screening assay to shortlist compounds from vast institutional libraries and synthetic capabilities. Drug discovery efforts focus on the following:

·           Target engagement and evaluation of efficacy with a particular target identity and quantitative evaluate drug binding to target proteins in cells and tissues. Quantitation of target engagement can be in terms of percentage. The ability of a quantitated extent of interaction to pro-duce the desired efficacy in animal models is assessed.

·           Molecule search is an interdisciplinary involvement of quantita-tive SAR (QSAR) assessment; in silico molecular modeling studies that try to assess molecular mechanism and location of engage-ment on the target, which can help guide QSAR efforts; and synthe-sis/generation of new molecules that can be tested based on these assessments.

·           Once one or more series of molecules have been identified with key structural features needed for target engagement and efficacy, lead optimization efforts focus on developability assessment (identifica-tion of any liabilities that can hinder development of the compound during later stages in the development) and appropriate modification of molecular design or delivery strategy design to enable the progres-sion of a molecule through later stages of drug development. These assessments also include dose projections, identification of appropri-ate route of drug administration, and an assessment of the observed or predictable liabilities of adverse effects.

The drug development studies follow the identification of a single lead molecule or drug candidate. These studies are aimed at formal toxicity assessment that can enable initiation of first-in-human (FIH) studies and at enabling clinical trials through various phases of drug development into generating the needed data package for the regulatory approval and com-mercialization. The details of the drug development studies will be a subject of the Chapter 2.

Sources of drugs

Identification of new molecules with the potential to produce a desired therapeutic effect involves a combination of (1) molecular physiology and pathophysiology; that is, research on the molecular mechanisms of biologi-cal process and disease progression; (2) review of known therapeutic agents; and/or (3) conceptualization and synthesis/procurement of potential new molecules that may also involve random selection and broad biological screening.

The sources of new drugs are varied (Figure 1.2). NMEs can be of synthetic or natural origin, the latter involving inorganic compounds or compounds purified from plants or animals.

Plant sources

Natural compounds extracted from plants have often provided novel structures for therapeutic applications. For example, vincristine is derived from the periwinkle plant Vinca rosea, etoposide is from the mandrake plant Podophyllum peltatum, taxol is from the pacific yew Taxus brevi-folia, doxorubicin is a fermentation product of the bacteria Streptomyces, l-asparaginase is from Escherichia coli or E. cartovora, rhizoxin is from the fungus Rhizopus chinensis, cytarabine is from the marine sponge Cryptotethya crypta, and bryostatin is from the sea moss Bugula neritina. Another example is paclitaxel (Taxol®), prepared from the extract of the pacific yew, used in the treatment of ovarian cancer. Digoxin is one of

Figure 1.2 Different sources of drug molecules.

the most widely used drugs in the management of congestive heart failure, weakened heart, and irregular heart beat (arrhythmia). The common garden plant, the foxglove or Digitalis purpurea, is the source of digoxin.

Organic synthesis

Chemical synthesis could involve (a) synthesis of analogs of natural compounds in an effort to improve affinity, specificity, or potency to improve the safety and efficacy profile of the original natural compound; (b) synthesis of a natu-ral molecule from a more abundantly available intermediate to reduce cost and/or improve purity (e.g., taxotere was developed to overcome the supply problems with taxol); or (c) synthesis of a new, unique chemical structure.

Synthesis of analogs of natural compounds is exemplified by the following: carboplatin—an analog of cisplatin with reduced renal toxicity, doxorubicin—an analog of daunomycin with lower cardiotoxicity, and topotecan—an analog of camptothecin with lower toxicity. Synthesis of analogs of known drugs is sometimes aimed at improving the targeting and the pharmacokinetics of a drug. The tauromustine couples a nitrosourea anticancer agent to a brain-targeting peptide. Synthesis of new molecular entities (NMEs) that are analogs of known compounds or completely novel structures involves computer modeling of drug–receptor interactions, followed by synthesis and evaluation by using tools such as solid-state and combinato-rial chemistry. For example, methotrexate and 5-fluorouracil were developed as analogs of natural compounds that demonstrated anticancer activity.

Use of animals

The use of animals in the production of various biologic products, includ-ing serum, antibiotics, and vaccines, has life-saving significance. Hormonal substances, such as thyroid extract, insulin, and pituitary hormones obtained from the endocrine glands of cattle, sheep and swine, are life-saving drugs used daily as replacement therapy.

Genetic engineering

In addition to the use of whole animals, cultures of cells and tissues from animal and human origin are routinely used for the discovery and devel-opment of new drugs—both small molecules and biologicals, such as vaccines. Drugs that were traditionally produced in animals are increas-ingly being synthesized by using cell and tissue cultures. The two basic technologies that drive the genetic field of drug development are recombi-nant DNA technology and monoclonal antibody production. Recombinant DNA technology involves the manipulation of cellular DNA to produce desired proteins, which may then be extracted from cell cultures for thera-peutic use. Recombinant DNA technology has the potential to produce a wide variety of proteins. For example, human insulin, human growth hormone, hepatitis B vaccine, and interferon are produced by recombinant DNA technology.

A growing class of biologics is monoclonal antibodies against cellu-lar targets aimed for destruction, such as molecular markers on tumors. Monoclonal antibodies target a single epitope, an antigen surface recog-nized by the antibody, as against natural polyclonal antibodies, which bind to different epitopes on one or more antigen molecules. This confers a high degree of specificity to monoclonal antibodies. While recombinant DNA techniques usually involve protein production within cells of lower animals, monoclonal antibodies are produced in cells of higher animals, sometimes in the patient, to ensure the lack of patient immune reaction against these macromolecules on administration. Monoclonal antibodies are used as anti-cancer therapeutics, in home pregnancy testing products, and for drug tar-geting to specific sites within the body. In home pregnancy testing products, the monoclonal antibody used is highly sensitive to binding at one site of the human chorionic gonadotropin (HCG) molecule, a specific marker to preg-nancy because HCG is synthesized exclusively by the placenta.

Gene therapy

Gene therapy is the process of correction or replacement of defective genes and has the potential to be used to prevent, treat, cure, diagnose, or miti-gate human disease caused by genetic disorders. Oligonucleotides and small interfering RNA (siRNA) are used to inhibit aberrant protein production, whereas gene therapy aims at expressing therapeutic proteins inside the body.

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