Contemporary Accounts in Drug Discovery and Development

Like the first edition, this edition of Case Studies in Modern Drug Discovery and Development covers almost all aspects of the drug discovery process with detailed examples to showcase the science and technology; thus, it essentially will be suitable for all levels of scientists who are involved in drug discovery. The main targeted readers are medicinal chemists, and undergraduate and graduate students who are interested in drug discovery. Since it not only traces the drug discovery process from idea to marketed drug with a detailed explanation of the application of modern drug design principles and discovery technologies, but also showcases the importance of cross‐disciplinary applications of knowledge from different fields such as computer science and statistics, Contemporary Accounts in Drug Discovery and Development essentially will be beneficial to any scientist involved in the drug discovery process. It is also designed to be used as a textbook in a medicinal chemistry class. The book has 15 chapters and fits one full semester. With the comprehensive information included in each independent chapter, it is also suitable for professional seminars or courses that relate to drug design. Some of the drug discovery stories collected in this book are popular and life‐saving medications, so it will be of interest to the public who want to learn more about how these drugs are discovered.

Editing a scientific book is not an easy process; it took more than three years from the conception of the book, author recruiting, and chapter editing to the publication of the book. During this long process, there are many friends and colleagues who helped to make it possible. We would like to thank our editor, Jonathan Rose, for initiating the process, giving us the opportunity, and trusting us in editing Contemporary Accounts in Drug Discovery and Development . We also want to thank Wiley Managing Editor Dr. Andreas Sendtko for his role as a consistent point of contact both during the writing phase and right through to publication. His support has made the book‐editing process run very smoothly. We would also like to thank all the authors who dedicated their time to contribute the chapters and their respective companies for permission to publish their work. Without their unselfish contributions, especially during an unprecedentedly difficult period of the COVID‐19 pandemic, it is almost impossible to accomplish such a daunting job. We salute them for their time, effort, persistence, and dedication. We continue to believe that all the chapters will have a very important impact on future drug discovery programs and benefit future scientists of this field for generations to come. We would like to thank the reviewers of our book proposal for their valuable suggestions and critiques. We would like to thank Dr. Wen‐Lian Wu for his inputs/comments on the Alzheimer's disease chapter and Dr. Shuangping Shi for her expert comments on Appendix A. Xianhai is indebted to his wife Dr. Hongmei Li and his children Alexander and Angelina for their support and understanding. Bob would like to thank his wife Antoinette and his family for their encouragement and support over the years. Wayne is also grateful to the infinite support from his family.

The road to the discovery and development of life‐saving drugs is not and will never be easy and straightforward. With scientific advancements, technological innovations, close collaborations and knowledge sharing, and the lifetime dedication of pharmaceutical scientists and academic medical researchers, it is possible to improve the efficiency of drug discovery and development to deliver the therapies that will alleviate suffering and extend lives. We hope that this book can serve as a small stepping stone in this complex process and help the readers to contribute to the improvement of the health of humanity.

New Jersey, February 2022

Xianhai Huang Robert G. Aslanian Wayne H. Tang

Robert AbelDrug Discovery Group Schrödinger Inc. New York USA

Robert AslanianDepartment of Chemistry New Jersey City University Jersey City USA

Corina BeckerResearch & Development, Pharmaceuticals Bayer AG Wuppertal Germany

Andrea BortolatoResearch and Development, Computer‐Assisted Drug Design, Molecular Discovery Technologies Bristol Myers Squibb Princeton USA

David Yu‐Kai ChenDepartment of Chemistry Seoul National University Seoul South Korea

Yun DingEncoded Library Technologies/NCE Molecular Discovery GSK Cambridge USA

Wu DuHinova Pharmaceuticals Inc. Chengdu People’s Republic of China

Markus FollmannResearch & Development, Pharmaceuticals Bayer AG Wuppertal Germany

Jeffrey J. HaleAssociate Vice President Discovery Chemistry Merck & Co., Inc. West Point USA

Amy HanR&D Chemistry, Therapeutic Proteins Regeneron Pharmaceuticals, Inc. Tarrytown USA

Junliang HaoDiscovery Chemistry Research and Technologies Lilly Research Laboratory Eli Lilly and Company Lilly Corporate Center Indianapolis USA

Timothy P. HeffronDiscovery Chemistry Genentech, Inc. South San Francisco USA

Xianhai HuangDiscovery Chemistry InventisBio Co., Ltd. Florham Park USA Wenping LiTranslational Imaging Merck Research Laboratories West Point USA

Jonathan S. MasonSosei Heptares Steinmetz Building Granta Park Cambridge UK

Lothar RoessigResearch & Development, Pharmaceuticals Bayer AG Wuppertal Germany

Laurent SalphatiDrug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco USA

Peter SandnerResearch & Development, Pharmaceuticals Bayer AG Wuppertal Germany

Tomi SawyerMaestro Therapeutics Southborough USA

Sarah K. ScottEncoded Library Technologies/NCE Molecular Discovery GSK Cambridge USA

Hong C. ShenDepartment of Medicinal Chemistry, Therapeutic Modalities Roche Innovation Center Shanghai Shanghai People’s Republic of China

Steven T. StabenDiscovery Chemistry Genentech, Inc. South San Francisco USA

Johannes‐Peter StaschResearch & Development, Pharmaceuticals Bayer AG Wuppertal Germany

Wayne Haifeng TangDrug Discovery Group Schrödinger Inc. New York USA

Ling TongDiscovery Chemistry Merck Research Laboratories Kenilworth USA

Song YangDepartment of Medicinal Chemistry Therapeutic Modalities Roche Innovation Center Shanghai Shanghai People’s Republic of China

Hongying YunDepartment of Medicinal Chemistry Therapeutic Modalities Roche Innovation Center Shanghai Shanghai People’s Republic of China

Wei ZhuDepartment of Medicinal Chemistry Therapeutic Modalities Roche Innovation Center Shanghai Shanghai People’s Republic of China

Ning ZouR&D Chemistry, Therapeutic Proteins Regeneron Pharmaceuticals, Inc. Tarrytown USA

Jeffrey J. Hale

Discovery Chemistry, Merck & Co., Inc., 770 Sumneytown Pike, PA 19486‐004, West Point, PA, USA

As we approach the end of the second decade of the twenty‐first century, global human health faces significant challenges. In May 2018, the World Health Organization (WHO) reported that more than half of recent deaths worldwide were attributable to 10 major causes [1]. Mortality following from cardiovascular disorders, such as ischemic heart disease and stroke, figured prominently on that list, while conditions such as chronic obstructive pulmonary disease, dementias, and diabetes were noted to have increased in frequency since 2000. While the prevalence of deaths from non‐communicable diseases may be perceived to be of greater concern in high‐income countries, the WHO noted that “diseases of aging” are significant globally. In September 2018, the International Agency for Research on Cancer noted the increasing prevalence of cancers worldwide, with an expectation at current rates that one in five men and one in six women will develop cancer during their lifetime, and one in eight men and one in 11 women die from it. Outbreaks of infectious diseases (e.g. dengue, Ebola, influenza, Zika) exacerbated by behavioral and social factors, as well as the associated issue of growing antimicrobial resistance, highlights another acute threat to human health [2]. The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in late 2019/early 2020 and the subsequent world‐wide pandemic that ensued was an extremely sobering reminder of this latter point [3]. A 2017 report from the United States Bureau of Vital Statistics indicated that life expectancy (all source mortality) may be leveling off or even decreasing, after close to a century of increase in this metric [4]. All told, a significant opportunity is before us to identify new methods to prevent, modify and treat disease and reverse the course of these human health trends.