Drug Discovery and Biotechnology - Research Paper Example

Biotechnology Pharmaceuticals and/ or biotechnology companies spend billions and take an average of ten to fifteen years to discover and bring a new drug to the public. The drug discovery and development process ensures that only safe and effective pharmaceutical products are brought to the market. Pharmaceutical companies follow similar pathways for the discovery of drugs. Although each company has its own standards and measures for measuring successful drug discovery, the most appropriate measures are ensured to meet safety and effectiveness standards in patients with little compound attrition. Keywords: Pharmaceuticals, Drugs, Drug discovery, Drug development, Pathways, Standards, Measures, Patients, Target, Genes, Compounds, Models, Strategies, Processes, Approaches, Candidate drugs Drug Discovery In the discover y of drugs, cellular and genetic factors that play a role in specific diseases are identified by scientists, chemists and pharmacologists. A search is carried out for chemical and biological substances targeting biological markers and likely to have drug-like effects. Out of the many new compounds identified during the discovery process, a few are clinically evaluated and considered safe for testing in humans. Further clinical testing is done and effective compounds are approved for treatment. There are many new scientific approaches being used to identify targets and obtain lead compounds. They include the use of synthetic chemistry, genomic and proteomic technology, laboratory automation, recombinant DNA and bioinformatics. Drug discovery involves numerous expertises. Various departments involved in drug discovery include: 1. Research and development: They are responsible for finding new compounds and examining them to ensure that they are safe enough to test in humans. 2. Medicinal chemists: They prepare new chemical substances which are screened for biological activity; they also prepare new leads in amounts sufficient for advanced testing. 3. Pharmacology, molecular biology and screening: They evaluate each new chemical entity in a set of high throughput screens. 4. Safety evaluation: They are meant to prove that new chemical entities and metabolites do not accumulate or cause harm during short term administration. 5. Process research: They manufacture enough new chemical entities for advanced testing and development of dosage form. 6. Legal affairs: They write up and file patents to protect company inventions. 7. Research administration: They collect materials generated by all departments and lay them out into requests for exemption so that new chemical entities can be tested in humans. The following diagram highlights the steps involved in the drug discovery process: The following steps highlight the activities that result in development of new drugs; 1. Target Discovery Target Discovery is also known as Target identification. Drug discovery and development mainly follows two paradigms namely; a. Physiology based drug discovery: It follows physiological readouts where compounds are screened and profiled based on the read out. Purely physiology-based approaches jump right into screening, identification of drug target and action mechanism follows in later stages. This is done through deduction based on the specific pharmacological properties that lead compounds poses. b. Target-based drug discovery: Identification of the function of a possible therapeutic target and its role in disease is done first. This is sometimes a difficult task, given the huge number of human or pathogen genes and the different types of their gene products. The key difference between these paradigms lies in the time point at which the drug target is identified. Understanding the mechanism of a disease guides research and develops a possible treatment to reverse the disease process. Disease mechanisms can be classified into genetic disorders, infection by bacteria, fungi or viruses, immune or autoimmune disease, trauma and acute disease based on organ failure or injury and multicausal disease. Particular gene defects that cause hereditary disorders have been identified in a number of diseases. Advancements in DNA sequencing technology have facilitated prompt identification of disease genes through genetic screening. Targets for therapeutic intervention include proteins and enzymes, receptors, DNA, RNA and ribosomal targets. A number of parameters for example development of resistance, cellular location and transport mechanisms influence the drugability of a given target. Functional genomics have been applied to determine disease mechanisms and identify disease genes and disease markers. They utilize a lot of information requiring sophisticated statistical analysis and this has accelerated the discipline of bioinformatics. 2. Target Validation Target validation is also known as Target Prioritization. Researchers analyze and compare each drug target to others based on their association with a specific disease and their ability to regulate biological and chemical compounds in the body in order to select targets most likely to be useful in the development of new treatments for a disease. Targets are validated with in vivo and in vitro models that involve studies in whole animals or disease-related cell based models. These provide information about the unifying response of an organism to a pharmacological intervention and help in predicting the possible profile of new drugs in patients. Transgenic animals whose target gene is knocked out have become a vital approach to experiments in the determination of gene functions in a whole organism. Research to define pathways controlling and regulating processes in living organisms provides vital information for drug discovery. Knowledge of pathways and interrelations helps researchers understand profiles of side effects. Identifying one disease target leads to a number of alternative drug targets in a similar pathway increasing possibilities for a novel therapeutic for example drugs acting on the pathway of cholesterol synthesis. 3. Lead Identification Lead identification begins with the development of an assay, followed by screening of compound libraries; the quality of data is determined by the quality of an assay. The assay used should be relevant, reliable, practical, feasible, automated and cost effective. Identification of suitable lead compounds for successive optimization is a key requirement in drug discovery. A lead substance or compound is believed to have the potential to treat diseases. The compound is generally selected from libraries containing thousands of compounds. High throughput screening rapidly sorts through many compounds to those that bind to a receptor or enzyme with high strength and activity as well as those that do not. The method shows how selective every compound is for the relevant target. Once highly effective compounds have been found, expert systems are used to assess for toxicity in a process called cross-screening. Potentially toxic compounds are removed to reduce risk of later stage failures that could cause delays in drug development or cost billions to pharmaceutical companies. Expert systems are also used to rank and prioritize compounds for safety and selection of compounds to be tested first. Many chemicals are discarded at this stage and successful ones taken into lead optimization and modification. Chemical genomics-driven approaches have been successful strategies in lead finding. Comprehensive scientific understanding of the interrelationship between biological and chemical information is important for success in earlier compound identification. The lead identification strategy is therefore driven by relationships between specific chemo types and biological targets within target families. Chemical genomics or chemo genomics seeks to bridge this chemical and biological space. 4. Lead Optimization Lead optimization is an elaborate, non-linear process. It involves refining the chemical structure of a known hit and improves its drug characteristics for production of a preclinical candidate. It uses combinatorial, empirical and rational approaches to optimise lead trough a continuous process with many steps applying knowledge gained at every stage. One or more known hits are examined in secondary assays and sets of related compounds known as analogs are synthesized and screened. The lead optimization process is repetitive, at some point; new analogs are fed back into the screening process for determination of strength, selectivity and action mechanism. The lead optimization process continues until a defined drug profile warranting testing of new drugs in humans is achieved. Formulation problems and solutions influencing design of lead molecules are fed back into the repetitive lead optimization cycle together with preclinical and clinical examinations. Formulation substances not recognized to be safe are become part of safety assessment and their PK, PD or ADME behavior and toxicity profile are documented in the investigational new drug application. 5. Preclinical Testing It involves in vitro and in vivo tests. In vitro tests are carried out in laboratories using beakers and test tubes. In vivo tests are carried out in living cell cultures and animal models. They studies are meant to provide an understanding of how a drug works and its safety profile. Researches work on how to scale up drugs to large quantities for clinical trials. Drug Development An investigational new drug application is filed before researchers begin any new clinical trials. Results of preclinical work, candidate’s drug chemical structure and its work in the body and side effects and manufacturing information are included in the investigational new drug application. Clinical Trials fall into three phases: 1. Phase one: Candidate drugs are tested in humans for the first time. The goal of this is to discover if a drug is safe in humans. Studies are conducted with a small group of healthy volunteers. Pharmacodynamics of a drug is studied. 2. Phase two: Tests are carried out in a small group of patients with the disease or condition under study. The candidate drug effectiveness is evaluated and possible short term side effects and risks associated with the drug are examined. 3. Phase three: Tests are carried out in a large group of patients. Tests aim at determining whether a drug is safe and effective. Phase three trials are most expensive and take long periods. Drug Manufacturing There are clear differences in the manufacture of small and large molecule drugs. Manufacture of small drugs relies on organic chemical synthesis while large drugs rely on biological systems of recombinant DNA technology. Drug development which covers discovery and commercial production of a drug is undertaken before large scale manufacturing of a drug. Increasing quantities of drug material are required; demand gradually grows from minigrams to kilogram levels. Initially, drugs are produced on a laboratory scale, production then progresses to pilot plant scale to make more drug material available for clinical trials. Finally production implements methods, processes, equipment and setting up of a manufacturing plant for large scale production of drugs for commercial use. Development approaches cover the following general items: 1. Raw materials: They have a meaningful impact on the drug manufacturing process. Raw materials need to be available, reliably supplied, reactive, toxic, handled and stored well. Costs in obtaining raw materials, manufacturing and yields are also considered. 2. Safety: An appropriate manufacturing process is determined to ensure safety and purification. 3. Reproducibility of manufacturing processes: Procedures and processes employed in large scale manufacturing processes to ensure drug products conforms with anticipated safety, effectiveness, purity, potency and consistency on a regular basis are evaluated. 4. Environmental factors: Manufacturing plants must comply with local environmental legislation. Set up of manufacturing plants should include systems for control of gas emissions, solid waste decontamination and liquid discharge treatment. Manufacturing of drugs must comply with regulations of Good Manufacturing Practices. References Gupta, S. K. (2011). Drug Discovery and Clinical Research. New Delhi: Jaypee brothers’ medical publishers. Rick, N. (2011). Drugs: From Discovery to Approval (2nd ed.). Hoboken: John Wiley and sons. Livingstone, D. J. (2011). Drug Design Strategies: Quantitative Approaches. London: RSC publishing.  Kubinyi, H., Müller, G., Mannhold, R., & Folkers, G. (2004). Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective. Weinheim: Wiley-VCH.   Pharmaceutical research and manufacturers (2007). Drug discovery and development: understanding the R & D process. Washington DC: Hughes et al. Pharmaceutical product development. Retrieved on March 23, 2012, from http://www.ppdi.com/about_ppd/drug_development.htm#2 Read More