Preface Free

I went to sleep one evening, very tired after a long, cold winter day in the hills of northwestern New Jersey. I felt like I could sleep for a thousand years… and then, like thunder, the thought struck my mind: if I did just that and woke up in the 30th century, what would drug discovery be like? How would it have changed? What diseases would still be incurable, and which ones will not exist anymore? And how would our current efforts be seen, in retrospect? I took the precaution of making a note of that idea, so that I would not forget (as it has happened in the past) and I could work on it the next morning.

Drug discovery is an interesting human endeavor in that nobody knows exactly how to succeed. We try different strategies hoping that the next time we will get it right. We swung from the purported, process-centered “industrialization” of the late 1990's to the explosion of innovation of the 2010's. When I began my pharmaceutical research career we worked in ultra-secretive laboratories in buildings without windows to preclude anyone walking outside from getting the slightest idea of what we were doing indoors. In contrast, openness is now flourishing and precompetitive collaborations are a necessity today, as alliances are forming at a high pace to integrate emerging knowledge generated in academia into industrial new drug projects. This interdependence among different sectors in the “Life Science Ecosystem” is key to the future of drug discovery.

As a testament to that spirit, this book is co-authored by scientists from academia and industry, roughly in equal proportion. And we, the co-authors, come from many different scientific fields, such as molecular pharmacology, cell biology, medicinal chemistry, computational chemistry, and chemical biology. Working together we are trying to make the future come faster. This spirit of collaboration should not be taken for granted, and I sincerely hope it is nurtured and developed for the next thousand years by future generations of scientists.

This book aims to be a time capsule documenting the initial stages of applying allosteric modulation principles to drug discovery. Allosterism has been known for some 50 years. However, it is relatively recently that we started trying to incorporate it systematically into our arsenal of drug modalities. As allosterism is broadly seen in nature, we are presenting examples from the work of experts in areas such as enzymes, transporters, ion channels, and G-protein-coupled receptors. I suspect allosterism will become a stepping stone in our journey to understanding human life at the molecular level.

Diversity of thought is an important component in the creation of new scientific knowledge. All authors have been challenged to present their most advanced views in their field of expertise. They were also given complete freedom to express their perspectives in areas that are constantly expanding. Every single one of them took the risk, and all deserve credit for doing so. With that in mind, I hope the reader will gain diverse, and perhaps not always converging, insight coming from many different perspectives gained throughout our efforts to understand allosterism. In editing this work, I have aimed to preserve a feeling that these are our current best approaches to study allosterism in drug discovery, but knowing that we still have a lot to learn. Indeed, I personally have greatly broadened my own views on the topic and learned a lot from editing the input to this book and related scientific reports.

So, whether you are reading this in 2016 or in 3016, you should know that we, the co-authors, came together to get to the future as soon as possible. As long as the time to deliver a new drug treatment is measured in decades, every difference than we can make along the way could have tremendous impact on the lives of patients and their families. That is the sacrament of those working in drug discovery, always.

I am grateful to my fellow co-authors for joining me in this endeavor, which I hope they found rewarding and worthy of their time and efforts. I thank Harriet Manning, Rowan Frame, and Antonia Pass, from the Royal Society of Chemistry, for their guidance. Special thanks to Dr Dave Rotella – an excellent medicinal chemist and colleague – for the opportunity he gave me to lead this effort and interact together.

Finally, and humbly, I would like to acknowledge five mentors who had major impact in my professional and personal life over a number of years. In chronological order, the late Professor Eduardo G. Gros, the late Professor Derek H. R. Barton, Dr Bill Greenlee, Dr Frank Larsen, and Dr Al Robichaud supported, challenged, and inspired me. Without them, I would not be where I am today. Wherever you are, I hope you see a part of yourselves reflected in this work.

Dario Doller