Medicinal chemistry – making use of data, information, knowledge and using it to transform health care

Medicinal chemistry is the theme of this month’s issue of Drug Discovery Today’s Editor’s Choice newsletter. Medicinal chemistry is a complex science at the heart of drug discovery, drug design and drug hunting. It is the art of generating ‘molecules with function’ - lead compounds with potential for future drugs and optimizing these iteratively into medicines for unmet medical need.

Owing to the vastness of drug-like and biologically relevant space in addition to the variety of drug target classes, target locations and disease types which the compounds will be designed to treat, each drug discovery program will face challenges during the hit-to-candidate drug phase, many of which can only be addressed bymedicinal chemistry. Here, medicinal chemists willuse their knowledge and the available data to design new compounds that avoid or solve problems or overcome current challenges and boundaries to deliver differentiated molecules that could innovate healthcare.

Despite of over half a century of medicinal chemistry practice, one might say that the science has only started to mature, with the multidimensionality of property-activity based lead optimization being reasonably understood and practiced relatively recently. Nevertheless, to improve success rates, reduce attrition and sustain productivity in an increasingly challenging environment in drug discovery, medicinal chemists must effectively use the data available for prospective drug design, continue to develop their drug hunting skills, keep learning from experience, effectively capture the knowledge created and explore new strategies and paradigms. Furthermore, medicinal chemists ought to capitalize on the tremendous potential for innovation of this entrepreneurial science by actively exploring new arenas and scientific interfaces in which their ‘molecules with function’ can make a difference to human healthcare.

The first of the four free downloads is an article by Timothy J. Ritchie, Peter Ertl and Richard Lewis from Novartis titled ‘The graphical representation of ADME-related molecule properties for medicinal chemists’. Successful small molecule drugs are compounds which, further to their unique biological potency, manage to balance other molecular properties which make them have attractive pharmacokinetic profiles, are well tolerated and safe. Owing to the limited ability of humans to track data of more than three dimensions simultaneously, the available data (whether calculated or measured) is often not effectively used during lead optimization. The authors review various elegant graphical representations for the multidimensional parameters that are influenced by chemical structure and need to be tracked or optimized during a lead optimization program. For example, simple radar plots or molecule ‘healthiness’ traffic light pie charts can be rapidly generated providing guidance to the chemist on the risk and probability of a compound to face later challenges owing to certain extreme molecular properties.

The second article by David R. Cheshire ‘How well do medicinal chemists learn from experience?’ discusses an analysis from AstraZeneca on lead optimization campaigns reaching candidate drugs, the level of redundancy in compound generation and the generation of a database to capture and track project information and challenges solved. The article provides a definition of a chemical series as a ‘distinct set of compounds that contain a common structural motif that consistently provide the analogs with the same unique advantage’ and shows that a candidate drug is typically an early member of a larger series, encouraging chemists to keep looking for new structural step changes after a first candidate drug is identified or a certain number of compounds are synthesized. The author also discloses MeCKS, a proprietary database that can capture the current status, emerging issues and solutions in active chemistry programs.

The third article ‘ROCK: the Roche medicinal chemistry knowledge application – design, use and impact’ written by colleagues (Urs Hofer, Patrick Schnider, Fausto Agnetti, Guido Galley, Patrizio Mattei, Matt Lucas and Hans-Joachim Boehm) and me discusses medicinal chemistry knowledge capture and its dedicated application (ROCK) at Roche. Far more than a Wiki, ROCK enables chemists to browse curated categories, search free text and controlled keywords all in combination with chemical (sub)structures for knowledge gained in solving challenges encountered in previous programs. It now enables medicinal chemists to draw on an impressive volume of distilled knowledge across categorized internal and external knowledge for prospective drug design, identifying potential structural issues early and providing guidance on the variety of ways of how previous teams have successfully dealt with challenges.

The final article ‘The future of discovery chemistry: quo vadis? Academic to industrial – the maturation of medicinal chemistry to chemical biology’ by Torsten Hoffmann and Cheryl Bishop presents findings from discussions at Roche on the future roles and impact of medicinal chemistry within an industrial organization, illustrating two potential paths. The authors encourage medicinal chemists to pursue innovative goals and balance efficiency and innovation. The entrepreneurial medicinal chemist ought to broaden the discipline to chemical biology while maintaining close feedback from clinical development.

Overall the articles illustrate that to be a successful drughunter the medicinal chemist needs to effectively visualize and use the data available, draw upon previous information and knowledge to predict properties, avoid inefficiencies and redundancies and also explore new ways in which the experience and expertise can be used to explore scientific boundaries, interface better with biology and impact healthcare.

Dr Alexander Mayweg is currently Head of Medicinal Chemistry at Roche Pharma Research and Early Development China in Shanghai. Prior to this role he was a section head at Roche in China and group leader and lead chemist at Roche in Basel Switzerland where he led several research programs across various target classes and disease areas, having started his career in medicinal chemistry in Basel in 2003. He also led the team to create a knowledge capture application which was awarded the Roche Olympiad Gold Medal award in 2007. His research interests include structure and/or fragment based drug design, chemical biology, knowledge capture, compound file library design, therapeutic peptides, computational chemistry and academic outreach. In 2011 he was awarded the EFMC prize for young scientists in industry. Alexander was trained as a synthetic organic chemist receiving a B.Sc. degree from Imperial College, a D.Phil. from Oxford and a Post-Doc from Stanford.

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