The discovery of macromolecular targets for bioactive agents is currently a bottleneck for the informed design of chemical probes and drug leads. Typically, activity profiling against genetically manipulated cell lines or chemical proteomics is pursued to shed light on their biology and deconvolute drug–target networks. By taking advantage of the ever-growing wealth of publicly available bioactivity data, learning algorithms now provide an attractive means to generate statistically motivated research hypotheses and thereby prioritize biochemical screens. Here, we highlight recent successes in machine intelligence for target identification and discuss challenges and opportunities for drug discovery.
The human gastrointestinal tract hosts almost a trillion microorganisms, organized in a complex community known as the gut microbiota, an integral part of human physiology and metabolism. Indeed, disease-specific alterations in the gut microbiota have been observed in several chronic disorders, including obesity and inflammatory bowel diseases. Correcting these alterations could revert the development of such pathologies or alleviate their symptoms. Recently, the gut microbiota has been the target of drug discovery that goes beyond classic probiotic approaches. This short review examines the promises and limitations of the latest strategies designed to modulate the gut bacterial community, and it explores the druggability of the gut microbiota by focusing on the potential of small molecules and prebiotics.
Photodynamic therapy (PDT) is an approved medical technique to treat certain forms of cancer. It has been used to complement traditional anticancer modalities such as surgery, chemotherapy or radiotherapy, and in certain cases, to replace these treatments. One critical parameter of PDT is the photosensitizer (PS); historically, a purely organic macrocyclic tetrapyrrole-based structure. This short review surveys two recent clinical examples of metal complexes, namely TOOKAD®-Soluble and TLD-1433, which have ideal photophysical properties to act as PDT PSs. We highlight the important role played by the metal ions in the PS for PDT activity.
For two decades, diversity-oriented synthesis (DOS) has facilitated the assembly of small-molecule libraries comprising a variety of complex molecular architectures. Here, we describe some of the recent achievements in this field, many of which promise to contribute to the development of new chemical probes and drug leads. In particular, we report progress along several avenues of bioactive discovery that leverage topographically complex compounds generated using DOS and other methods. We also discuss advances in DNA-compatible chemistry that enable syntheses of more three-dimensionally complex and diverse DNA-encoded libraries. Continual innovation in organic chemistry will be required to both expand and exploit our understanding of biological systems.
Dynamical features of cell signaling are the essence of living organisms. To understand animal development, it is fundamental to investigate signaling dynamics . Robust reporters are required to visualize spatial and temporal dynamics of enzyme activities and protein–protein interactions involved in signaling pathways. In this review, we summarize recent development in the design of new classes of fluorescent reporters for imaging dynamic activities of proteases, kinases, and protein–protein interactions. These reporters operate on new physical and/or chemical principles; achieve large dynamic range, high brightness, and fast kinetics; and reveal spatiotemporal dynamics of signaling that is correlated with developmental events such as embryonic morphogenesis in live animals including and zebrafish. Therefore, many of these reporters are great tools for biological discovery and mechanistic understanding of animal development and disease progression.
Stereotyped as a nexus of dNTP synthesis, the dual-subunit enzyme — ribonucleotide reductase (RNR) — is coming into view as a paradigm of oligomerization and moonlighting behavior. In the present issue of ‘omics’, we discuss what makes the larger subunit of this enzyme (RNR-α) so interesting, highlighting its emerging cellular interactome based on its unique oligomeric dynamism that dictates its compartment-specific occupations. Linking the history of the field with the multivariable nature of this exceedingly sophisticated enzyme, we further discuss implications of new data pertaining to DNA-damage response, S-phase checkpoints, and ultimately tumor suppression. We hereby hope to provide ideas for those interested in these fields and exemplify conceptual frameworks and tools that are useful to study RNR's broader roles in biology.
Understanding the molecular mechanisms of endogenous and environmental metabolites is crucial for basic biology and drug discovery. With the genome, proteome, and metabolome of many organisms being readily available, researchers now have the opportunity to dissect how key metabolites regulate complex cellular pathways . Nonetheless, characterizing the specific and functional protein targets of key metabolites associated with specific cellular phenotypes remains a major challenge. Innovations in chemical biology are now poised to address this fundamental limitation in physiology and disease. In this review, we highlight recent advances in chemoproteomics for targeted and proteome-wide analysis of metabolite–protein interactions that have enabled the discovery of unpredicted metabolite–protein interactions and facilitated the development of new small molecule therapeutics.