Chapter 25 - New challenges in drug discovery

Abstract

Drug discovery is a process by which novel potential medicines are identified via a series of critical research activities. It comprises a variety of scientific fields, including pharmacology, medicinal chemistry, biochemistry, and biology. The drug discovery centers and industries have supplied several life-saving medications for decades, which contribute to novel treatment opportunities for several life-threatening diseases. A central aim of the initiatives for drug discovery is to identify new molecular entities that can be useful in the management of diseases with unsatisfied needs. These conditions do not have useful treatments and, in fact, or potentially, constitute life threats. Many disorders, particularly acute diseases, can now be treated and managed properly. New drugs for heart disease, metabolic disorders, osteoporosis, mental health problems, oncology, gastrointestinal issues, reproductive health care, viral infections, etc. have been discovered to improve the health and quality of life. The entire procedure of drug discovery is a very complicated, time-consuming, expensive, and financially risky effort. Nowadays, drugs are produced via different naturally occurring resources, both traditionally or by various innovative techniques (Figure 25.1). Normally, it takes 10–15 years and requires the application of even over 2.5 billion dollars to have a novel medication in the market. In terms of the research & development (R & D) process and the new drug application process (NDA), the drug development industry is restructuring worldwide. Many of the restructurings were driven by costs, often benchmarked by governments in the United States and Europe, to provide the best value to the public purse for the purchase of medicines for national medical services. During the early stages of the drug development process, large-scale and complex chemical libraries are examined to identify new hits (i.e., bioactive compounds, ligands, and biomarkers). The complete process of drug discovery and development is graphically represented in Figure 25.2. Traditional medicinal chemistry strategies are often combined with sophisticated structural-based drug design (SBDD) and ligand-based drug design (LBDD) methods for exploring the huge chemical and biological molecules mostly as a major element of hit-to-lead advancement, lead standardization, and development of new active compounds. It is well known that drug discovery changed. In the past 5 years, Big Pharma around the world has undergone significant restructuring, with large companies remaining in need of all their skills and knowledge. It started outsourcing research organizations, but now it has gone much even further into the digital world. The path from concept in the new world of drug discovery and the goal of patient benefit validation will be a joint effort. New therapeutic classes are generated based on scientific options and therapeutical needs of drugs like pain medication, sedatives, L-dopa, antimicrobial agents, bioactive molecules, immunotherapies, and other drugs. All these medications were developed within a chemical framework of drug therapy and medication. Historically procedure of drug discovery and development is as old as some of the oldest human cultures. Ayurveda practice in India and traditional Chinese medicines in China are still in practice with over 5000-year-old therapy. Since the time Edward Jenner discovered immunization against smallpox, the beginning of modern medicine is considered. The field developed gradually until 1928, when Sir Alexander Fleming discovered Penicillin after which the field of medicinal chemistry flourished and it became a complex interdisciplinary platform by the end of the twentieth century, mainly based on synthetic biological chemistry, which extended to multiple physiological specificities. Just at the beginning of the 21st century, research on drug discovery faced new challenges that transformed the classical concept of drug development that had taken place over half a century in practice. Pharmaceutical firms have therefore settled policies to address these problems and identified many key success features. While there are significant obstacles to marketing new drugs, it is a trend in the past 15 years that the number of drug approvals has increased. The Food and Drug Administration (FDA) authority approved an average of 43 drugs in 2014–18, compared to an average of 23 in the first decade of the century. Researchers regard 2018 as a successful year with almost 59 FDA-approved drugs. Though impressive, these figures must be seen as part of total research and development (R&D) spending in the pharmaceutical sector. As a result, in 35 years, efforts to find and develop new drugs have been doubled. We are still a long way behind this pursuit, despite progress and heavy investment. The concern is that there seems to be something wrong in this translation from precise early discovery experiments to translations in different animal models and clinical trials. All the high molecule assumptions focus on various methods for the mapping of chemicals and wet lab goals, including the target design of drugs, the creation of new targets and implementing existing targets, and the launch of special molecules from multiple perspectives, on a synthetic route and the biodiversity test for novel drugs, appeared to be failed. Despite high promising activities in the in-vitro models, the drop-off of molecules when transported through the development chain is high. In recent years, countless emerging innovations and concepts have emerged for drug discovery. Besides the onset of each new method, a commitment was made to generate better drugs while reducing or containing costs. At least to some degree, these techniques have been employed in most pharmaceutical companies. During the same period, industry management has been greatly pressured by shareholders and investors to increase drug development and innovation productivity to meet annual growth expectations. The most noticeable methods to cure have already been tried and often failed for many diseases. During the same period, industry management has been greatly pressured by shareholders and investors to increase drug development and innovation productivity to meet annual growth expectations. The most noticeable methods to cure have already been tried and often failed for many diseases. For the development and evaluation of new medicines, the complexity of human biology also presents many challenges. Drug molecules with activity specific to one unique biological pathway in diseased cells with an optimal beginning and/or duration of action pharmacokinetic profile or without side effects as a result of systemically exposed conditions are very difficult to design. Patient compliance can also be a significant challenge when taking medicines. Drug delivery systems allow the design and engineering level of control to overcome these challenges beyond the inherent properties of the drug molecule. The old ways of finding drugs have passed forever and surely nobody wants to go back to packing and running columns manually. The trend we presently see for the large pharmaceutical chemist to become a multidisciplinary drug explorer at the core of a global discovery web. Some common challenges in the field of drug discovery are described in the following sections.