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Activity‐directed synthesis (ADS) is a structure‐blind, functional‐driven molecular discovery approach. In this Concept, four case studies highlight the general applicability of ADS and showcase its flexibility to support different medicinal chemistry strategies. ADS deliberately harnesses reactions with multiple possible outcomes, and allows many chemotypes to be evaluated in parallel. Resources are focused on bioactive molecules, which emerge in tandem with associated synthetic routes. Some of the future challenges for ADS are highlighted, including the realisation of an autonomous molecular discovery platform. The prospects for ADS to become a mainstream lead generation approach are discussed., Parallel discovery of diverse bioactive small molecules for a range of targets: Activity‐directed synthesis has enabled a range of medicinal chemistry strategies to be realised, including scaffold constraint; fragment‐based discovery; expansion of a series of ligands; and scaffold hopping. Future scientific challenges, and the prospects of activity‐directed synthesis becoming a mainstream lead generation approach, are discussed.

The search for new bioactive molecules remains an open challenge limiting our ability to discover new drugs to treat disease and chemical probes to comprehensively study biological processes. The vastness of chemical space renders its exploration unfeasible by synthesis alone. Historically, chemists have tended to explore chemical space unevenly without committing to systematic frameworks for navigation. This minireview covers a range of approaches that take inspiration from the structure or origin of natural products, and help focus molecular discovery on biologically-relevant regions of chemical space. All these approaches have enabled the discovery of distinctive and novel bioactive small molecules such as useful chemical probes of biological mechanisms. This minireview comments on how such approaches may be developed into more general frameworks for the systematic identification of currently unexplored regions of biologically-relevant chemical space, a challenge that is central to both chemical biology and medicinal chemistry.

Biology-oriented-synthesis (BIOS), is a chemocentric approach to identifying structurally novel molecules as tools for chemical biology and medicinal chemistry research. The vast chemical space cannot be exhaustively covered by synthetic chemistry. Thus, methods which reveal biologically relevant portions of chemical space are of high value. Guided by structural conservation in the evolution of both proteins and natural products, BIOS classifies bioactive compound classes in a hierarchical manner based on molecular architecture and bioactivity. Biologically relevant scaffolds inspire and guide the synthesis of BIOS libraries, which calls for the development of suitable synthetic methodologies. These compound collections have enriched biological relevance, leading to the discovery of bioactive small molecules. These potent and selective modulators allow the study of complex biological pathways and may serve as starting points for drug discovery programs. Thus, BIOS can also be regarded as a hypothesis-generating tool, guiding the design and preparation of novel, bioactive molecular scaffolds. This review elaborates the principles of BIOS and highlights selected examples of their application, which have in turn created future opportunities for the expansion of BIOS and its combination with fragment-based compound discovery for the identification of biologically relevant small molecules with unprecedented molecular scaffolds.1 Introduction2 Structural Classification of Natural Products3 Implications and Opportunities for Biology-Oriented Synthesis4 Applications of Biology-Oriented Synthesis4.1 Chemical Structure and Bioactivity Guided Approaches4.2 Natural-Product-Derived Fragment-Based Approaches5 Conclusions and Outlook

The identification of high-quality starting points for drug discovery is an enduring challenge in medicinal chemistry. Yet, the chemical space explored in discovery programmes tends be limited by the narrow toolkit of robust methods that are exploited in discovery workflows. The European Lead Factory (ELF) was established in 2013 to boost early-stage drug discovery within Europe. In this Feature, we describe an exemplar partnership that has led to the addition of 21 119 distinctive screening compounds to the ELF Joint European Compound Library. The partnership could serve as a blueprint for the translation of innovative academic chemistry into discovery programmes.

The principles guiding the design and synthesis of bioactive compounds based on natural product (NP) structure, such as biology-oriented synthesis (BIOS), are limited by their partial coverage of the NP-like chemical space of existing NPs and retainment of bioactivity in the corresponding compound collections. Here we propose and validate a concept to overcome these limitations by de novo combination of NP-derived fragments to structurally unprecedented 'pseudo natural products'. Pseudo NPs inherit characteristic elements of NP structure yet enable the efficient exploration of areas of chemical space not covered by NP-derived chemotypes, and may possess novel bioactivities. We provide a proof of principle by designing, synthesizing and investigating the biological properties of chromopynone pseudo NPs that combine biosynthetically unrelated chromane- and tetrahydropyrimidinone NP fragments. We show that chromopynones define a glucose uptake inhibitor chemotype that selectively targets glucose transporters GLUT-1 and -3, inhibits cancer cell growth and promises to inspire new drug discovery programmes aimed at tumour metabolism.

Biology oriented synthesis (BIOS), is an approach to efficiently identify compound classes to be used as probes or tools for chemical biology research as well as starting points for medicinal chemistry programs. As chemical space is enormously large and cannot be not be exhaustively covered using solely synthetic chemistry, methods which direct and pin-point biologically relevant areas are highly sought. Such methods would also serve as hypothesis-generating tools, inspiring the syntheses of novel, bioactive molecular scaffolds. Building on the notion of structural conservatism in the evolution of proteins and natural products, BIOS utilizes a hierarchical classification of bioactive compound classes depending on the structural and categorical classification of bioactivity, for instance using the Scaffold Hunter software as a navigational tool in chemical space. Biologically-relevant scaffolds inspire and direct the synthesis of BIOS libraries which have enriched bioactivities, facilitating the discovery of the highly sought after small molecules which allow the perturbation of complex biological phenomena and may serve as starting points for drug discovery programs. This chapter will elaborate on the underlying reasoning for the development of BIOS, as well as its current and possible future applications.

Small-molecule chemotypes with unexpected bioactivity may be identified by combining strategies built on the biological relevance of, e.g., natural products (NPs), such as biology-oriented synthesis, with principles that enable efficient coverage of chemical space, such as fragment-based compound design. Evaluation in target-agnostic phenotypic assays and target identification may link biologically relevant chemotypes to unexpected and unknown targets. We describe the phenotypic identification of an unprecedented kinase inhibitor chemotype obtained by synthetic combination of two biosynthetically unrelated NP fragment types. Target identification and biological characterization revealed that the inhibitor, termed Myokinasib, impairs cytokinesis, induces formation of multinucleated cells, and reduces phosphorylated myosin II light chain abundance on stress fibers by selective inhibition of myosin light chain kinase 1.

The structures and biological activities of natural products have often provided inspiration in drug discovery. The functional benefits of natural products to the host organism steers the evolution of their biosynthetic pathways. Here, we describe a discovery approach--which we term activity-directed synthesis--in which reactions with alternative outcomes are steered towards functional products. Arrays of catalysed reactions of α-diazo amides, whose outcome was critically dependent on the specific conditions used, were performed. The products were assayed at increasingly low concentration, with the results informing the design of a subsequent reaction array. Finally, promising reactions were scaled up and, after purification, submicromolar ligands based on two scaffolds with no previous annotated activity against the androgen receptor were discovered. The approach enables the discovery, in tandem, of both bioactive small molecules and associated synthetic routes, analogous to the evolution of biosynthetic pathways to yield natural products.