Cyclohexyl-griselimycin is active against Mycobacterium abscessus in mice

Cyclohexyl-griselimycin is a preclinical candidate for tuberculosis (TB). Here, we show that this oral cyclodepsipeptide is also active against the intrinsically drug resistant non-tuberculous mycobacterium Mycobacterium abscessus in vitro and in a mouse model of infection. This adds a novel advanced lead compound to the M. abscessus drug pipeline and supports a strategy of screening chemical matter generated in TB drug discovery efforts to fast track the discovery of novel antibiotics against M. abscessus .

Advances in Anticancer Drug Discovery

It has been an absolute pleasure to be the guest editor of this Special Issue! As the title indicates, the topic is on the advances made against cancer. Sixteen manuscripts were published, including eleven research papers and five reviews. The depth and width of the research presented is truly impressive, i.e., the detail of the biological processes within the cancer cells that are elucidated and the diverse nature of the chemical matter under investigation, spanning from heavy metals to small organic [...]

Selecting Approaches for Hit Identification and Increasing Options by Building the Efficient Discovery of Actionable Chemical Matter from DNA-Encoded Libraries

Over the past 20 years, the toolbox for discovering small-molecule therapeutic starting points has expanded considerably. Pharmaceutical researchers can now choose from technologies that, in addition to traditional high-throughput knowledge-based and diversity screening, now include the screening of fragment and fragment-like libraries, affinity selection mass spectrometry, and selection against DNA-encoded libraries (DELs). Each of these techniques has its own unique combination of advantages and limitations that makes them more, or less, suitable for different target classes or discovery objectives, such as desired mechanism of action. Layered on top of this are the constraints of the drug-hunters themselves, including budgets, timelines, and available platform capacity; each of these can play a part in dictating the hit identification strategy for a discovery program. In this article, we discuss some of the factors that we use to govern our building of a hit identification roadmap for a program and describe the increasing role that DELs are playing in our discovery strategy. Furthermore, we share our learning during our initial exploration of DEL and highlight the approaches we have evolved to maximize the value returned from DEL selections. Topics addressed include the optimization of library design and production, reagent validation, data analysis, and hit confirmation. We describe how our thinking in these areas has led us to build a DEL platform that has begun to deliver tractable matter to our global discovery portfolio.

The medicinal chemistry of mitochondrial dysfunction: a critical overview of efforts to modulate mitochondrial health

This manuscript reviews the compounds historically used to modulate mitochondria, and offers a perspective on which targets have been convincingly (in)validated with high quality chemical matter and those which remain untested.

Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking

ABSTRACTThe SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of diverse fragment libraries resulted in 214 unique macrodomain-binding fragments, out of 2,683 screened. An additional 60 molecules were selected from docking over 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several crystallographic and docking fragment hits were validated for solution binding using three biophysical techniques (DSF, HTRF, ITC). Overall, the 234 fragment structures presented explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

Document Embedding Centroids: New and Versatile Semantic Descriptors for Compounds

We describe a novel algorithm for generating representational embeddings of chemical matter based on the biomedical literature/semantic contexts in which they occur. We then demonstrate that these chemical descriptors have utility in nearest neighbor retrieval for early drug discovery tasks such as mechanism of action and target activity predictions.

Document Embedding Centroids: New and Versatile Semantic Descriptors for Compounds

We describe a novel algorithm for generating representational embeddings of chemical matter based on the biomedical literature/semantic contexts in which they occur. We then demonstrate that these chemical descriptors have utility in nearest neighbor retrieval for early drug discovery tasks such as mechanism of action and target activity predictions.