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We published the first edition of ‘The Handbook of Medicinal Chemistry: Principles and Practice’ in 2015, following in the footsteps of the perennially popular ‘Medicinal Chemistry Principles and Practice’. Both titles were designed to complement and support the biannual Royal Society of Chemistry Medicinal Chemistry summer school which has provided inspirational training to early career medicinal chemists and others entering the world of drug discovery for over 40 years.

For the 2015 edition, we considerably expanded the scope and content of its predecessor volumes, recognising the significant shifts in both the scientific practices and the nature of institutions engaged in drug discovery and development. We divided the book into three main sections: firstly, the fundamental principles used by the medicinal chemist; secondly, the application of those tools to progress molecules through discovery into development; and thirdly, case studies to demonstrate the reduction of these principles into practice. This volume was very well received and brought together for the first time in a single volume the key enabling information for the contemporary, practising medicinal chemist.

Given this impact, why then, only seven years later, is this second edition being published? What has changed in that time to make a new volume necessary?

Of course, the most striking illustration of the speed of scientific and industrial advance and change has been the phenomenal response to develop prophylactic and therapeutic strategies to coronavirus disease. Interestingly, this second edition was conceived before we knew about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the chapter writing and editing then has taken place in its shadow. The ability to respond rapidly to SARS-CoV-2 stemmed from the enormous technological and biological advances in recent years. These advances also underpin a plethora of new approaches making an impact in the discovery of new medicines.

The last seven years have seen new chemistry and synthetic methodology continuing to provide new opportunities for medicinal chemistry, alongside molecular biology developments which are providing new screening paradigms. In 2015 DNA encoded libraries were an emerging technology, they are now an established part of the lead generation canon – available from several CRO providers and even academic institutions. PROTACS, first proposed in 2001, were still an emerging modality in 2015, but have now exploded across the drug discovery landscape, with the first examples already in clinical testing. While QSAR was already a mature discipline, who would have guessed in 2015 that the combination of machine learning algorithms with artificial intelligence would bring de novo design, heralded by computational chemistry in the 1980s, back as a realistic prospect. Virtual screening, also not a new technique, has vastly expanded its scope through modern algorithms and cloud computing to explore virtual spaces of up to 1012 molecules and beyond. By 2015 we had already had the human genome in our hands for more than 13 years, but the acceleration and plummeting costs of whole genome sequencing are now providing vast data-sources of millions of human genome sequences aligned to patients' clinical data to mine for genes linked to diseases, providing medicinal chemists with new, better validated (although often more challenging) protein targets. Phenotypic screening has always been a rich source of chemical tools and while not as intellectually appealing as rational design, it has continued to find fascinating and important molecules like CFTR correctors which are changing the face of CF treatment. Molecular biology has been revolutionised by CRISPR/CAS9, providing more complex tools, providing genome-wide protein knockout, or activating screens to find new targets and even offering the concept of targeted genome editing as a new drug modality. Chemical biology continues to uncover subtle and revealing modes of action, which has opened up new fields, including exome skipping and RNA targeting, alongside uncovering small molecules acting as molecular glues and molecular glue degraders. Large-scale proteomics, and techniques such as CETSA, are enabling true in-cell target engagement and target deconvolution. In the field of structural biology, breakthroughs in equipment, instrumentation and computational power have meant cryogenic electron microscopy can now achieve resolutions suitable to impact drug discovery and open out structure-based drug design to previously unattainable target classes such as ion channels and macromolecular protein complexes. Then there is single-cell transcriptomics, hydrogen–deuterium exchange, acoustic mist mass spectrometry screening, high throughput imaging, the list goes on. So much has happened in seven years!

So apart from those subjects, which we have tried to incorporate, what else has changed in the second edition? Firstly, we have kept broadly to the overall structure of the first edition given the positive reception of its structure and logical flow from target and hit discovery through to clinical development. All the chapters have been revised and updated with new information, regulatory or legislative additions and exemplified with contemporary examples and case studies. We have three new chapters:

Synthetic chemistry – which reinforces the importance of the parent discipline of synthetic organic chemistry in the day-to-day job of the medicinal chemist and importantly uses synthesis as a tool to facilitate the preparation of key design molecules, as well as recognising the role of the chemist outside traditional ‘small molecule’ space.

AI and machine learning – to both establish its fundamental principles from QSAR analyses and helpfully delineate the hope from the hype and outline practical applications.

New modalities – which expands horizons beyond the ‘already drugged’ into the chemical space between traditional chemistry and biology – oligonucleotides, complex peptides, homo- and hetero-fused molecules (such as bi-specific antibodies, PROTACS etc.) as well as approaches to modify processing of RNA, DNA or protein synthesis.

Some of the approaches such as targeted protein degradation (via PROTAC or other modality), modification of RNA splicing, ability to visualise ligand-bound protein structures of membrane-bound proteins via cryo-EM, routine assessment of protein activity within the cell, are now so routine, it is hard to imagine them being outside the mainstream of drug discovery at the time of writing. Indeed, the inspiring case study we're delighted to be able to include describing risdiplam for the treatment of spinal muscular atrophy – and celebrated on the cover of this book – is testament to the fusion of new biological understanding opening up previously inconceivable approaches with excellence in medicinal chemistry and iterative lead optimisation.

For the Foreword, we were delighted that one of our industry's most influential commentators, Derek Lowe, author of the ‘In the pipeline’ blog, provides us with a perspective on medicinal chemistry.

Alongside the last edition we also published the medicinal chemistry toolkit iPad app. It was a joint initiative between the editors, Molmatinf and the RSC. This was a successful initiative making useful everyday tools freely available on a tablet as a secure environment. We received many requests for the app to be available on other platforms. So to accompany this edition, the editors and Molmatinf, sponsored by AstraZeneca Open Innovation, have ported the dose to man component of the iPad app to a freely available secure web app on the following link:

As stated in the preface to the first volume, the career of the medicinal chemist remains one of the most challenging and stimulating careers imaginable. The medicinal chemist, at the heart of a network of multidisciplinary scientists, can craft the beginnings of the journey towards a new medicine. And surely there could be no greater motivation.

We hope that this new edition will continue to train and inspire the next generation of drug discovers in the wide diversity of institutions and organisations that are striving to improve the quality of life for millions of people across the world.

Simon E. Ward and Andrew Davis

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