Jonathan B Baell
Future Med. Chem., 2021, 13(2), 91-93
https://doi.org/10.4155/fmc-2021-0005

Abstract

Welcome to this Early Career Special Focus Issue of Future Medicinal Chemistry. Assembled within is a veritable panoply of chemical biology discourses, showcasing the brilliance of our next generation of medicinal chemists and chemical biologists.
In ’Abiotic scaffolds in medicinal chemistry: not a waste of chemical space', Ronald W Brown (Bayer, Frankfurt, Germany) discusses ’abiotic’ and ’natural product-like’ scaffolds, presenting the overarching questions: Do complex abiotic scaffolds still hold a place in medicinal chemistry, and, if so, do they present unique advantages? Nicely, answers to these questions are to an extent left up to the reader to formulate based on the information provided. What is clear is that the European Lead Factory has encouraged application of newer synthetic methods that can provide 3D topologies previously inaccessible by Nature to populate chemical screening space with compounds that might have drug development characteristics. One imagines that compound libraries derived therefrom would tend to be focused and bespoke.
At the other extreme, new technologies are enabling construction of high-throughput screening libraries numbering in the billions. In ’The maturation of DNA encoded libraries: opportunities for new users', Conole et al. (Imperial College London, London, UK) pose the question of whether DNA-encoded libraries are feasible in academia and provide us a useful how-to guide for those outside pharmacology and interested in developing capability in this interesting technology. Or perhaps I should say "interesting technologies," as it becomes clear that this increasingly validated approach is blossoming with new developments. We are told that, conventionally, DNA-encoded libraries generally do not exceed more than three synthetic modifications, and so one could argue that a library that consists of a constant central scaffold lacks structural diversity. But then this is countered with the intelligent proposition that perhaps the ability to screen far larger numbers of compounds means that such constraints can be relaxed in DNA-encoded libraries, as screening may lead to higher affinity and a more elaborated hit. Nevertheless, the authors, recognizing the enormity of the theoretical chemical diversity space, sensibly view that library design would be best implemented by adopting the established guidelines for lead-like libraries.