A Chemical Biology View of Bioactive Small Molecules and a Binder‐Based Approach to Connect Biology to Precision Medicines

Schreiber, Stuart L.

doi:10.1002/ijch.201800113

Cited by 73 publications

(51 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…hemical probes are versatile tools to interrogate the functions of proteins in biological systems and complement genetic approaches 1 by producing reversible and graded gains or losses of protein activity, as well as, in certain instances, neo-functional outcomes [2][3][4][5] . Small molecules also represent a principal category of clinically approved drugs, and quality chemical probes are needed to pharmacologically characterize novel targets on the path to developing therapeutic agents.…”

mentioning

confidence: 99%

Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs

et al. 2019

View full text Add to dashboard Cite

A fundamental challenge in chemical biology and medicine is to understand and expand the fraction of the human proteome that can be targeted by small molecules. We recently described a strategy that integrates fragment-based ligand discovery with chemical proteomics to furnish global portraits of reversible small-molecule/protein interactions in human cells. Excavating clear structure-activity relationships from these 'ligandability' maps, however, was confounded by the distinct physicochemical properties and corresponding overall protein-binding potential of individual fragments. Here, we describe a compelling solution to this problem by introducing a next-generation set of fully functionalized fragments differing only in absolute stereochemistry. Using these enantiomeric probe pairs, or 'enantioprobes', we identify numerous stereoselective protein-fragment interactions in cells and show that these interactions occur at functional sites on proteins from diverse classes. Our findings thus indicate that incorporating chirality into fully functionalized fragment libraries provides a robust and streamlined method to discover ligandable proteins in cells.

show abstract

mentioning

confidence: 99%

Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs

et al. 2019

View full text Add to dashboard Cite

show abstract

“…DOS-DEL-1 contains approximately 100,000 compounds. Current DELs can theoretically contain >10 12 distinct compounds, 20 but evidence is lacking that larger numbers produce greater screening successes, and indeed there are suggestions that the opposite might be true. 44 We therefore focused on ensuring that our DNA barcodes were encoding the correct compounds (i.e., not reaction by-products or unreacted starting materials).…”

Section: Resultsmentioning

confidence: 99%

“…They may also change the dynamic properties of their targets, which can alter cellular half-lives (degraders and stabilizers), rates of post-translational modifications, or protein activities (e.g., by gaining neo-functions). 11,12 Binders can modulate protein behavior both as monovalent compounds [13][14][15] and as bivalent molecules in which two binders are covalently tethered. [16][17][18] Due to the challenges associated with DEL synthesis, many DNA-barcoded compounds exhibit a narrow range of structural features and architectures.…”

Section: Introductionmentioning

confidence: 99%

DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

Gerry

Wawer²,

Clemons³

et al. 2019

Preprint

View full text Add to dashboard Cite

It is challenging to incorporate stereochemical diversity and topographic complexity into DNA-encoded libraries (DELs) because DEL syntheses cannot fully exploit the capabilities of modern synthetic organic chemistry. Here, we describe the design, construction, and validation of DOS-DEL-1, a library of 107,616 DNA-barcoded chiral 2,3-disubsituted azetidines and pyrrolidines. We used stereospecific C–H arylation chemistry to furnish complex scaffolds primed for DEL synthesis, and we developed an improved on-DNA Suzuki reaction to maximize library quality. We then studied both the structural diversity of the library and the physicochemical properties of individual compounds using Tanimoto multi-fusion similarity analysis, among other techniques. These analyses revealed not only that most DOS-DEL-1 members have “drug-like” properties, but also that the library more closely resembles compound collections derived from diversity synthesis than those from other sources (e.g., commercial vendors). Finally, we performed validation screens against horseradish peroxidase and carbonic anhydrase IX, and we developed a novel, Poisson-based statistical framework to analyze the results. A set of assay positives were successfully translated into potent carbonic anhydrase inhibitors (IC50 = 20.1–68.7 nM), which confirmed the success of the synthesis and screening procedures. These results establish a strategy to synthesize DELs with scaffold-based stereochemical diversity and complexity that does not require the development of novel DNA-compatible chemistry.

show abstract

“…Chemical biology differs from small-molecule drug discovery, although organic compounds are developed in both fields [170,171]. Chemical biology plays a role in understanding the function of a target protein and serves as an important tool in target validation.…”

Section: Chemical Biologymentioning

confidence: 99%

A Practical Perspective on the Roles of Solution NMR Spectroscopy in Drug Discovery

Li¹,

Kang

2020

Molecules

View full text Add to dashboard Cite

Solution nuclear magnetic resonance (NMR) spectroscopy is a powerful tool to study structures and dynamics of biomolecules under physiological conditions. As there are numerous NMR-derived methods applicable to probe protein–ligand interactions, NMR has been widely utilized in drug discovery, especially in such steps as hit identification and lead optimization. NMR is frequently used to locate ligand-binding sites on a target protein and to determine ligand binding modes. NMR spectroscopy is also a unique tool in fragment-based drug design (FBDD), as it is able to investigate target-ligand interactions with diverse binding affinities. NMR spectroscopy is able to identify fragments that bind weakly to a target, making it valuable for identifying hits targeting undruggable sites. In this review, we summarize the roles of solution NMR spectroscopy in drug discovery. We describe some methods that are used in identifying fragments, understanding the mechanism of action for a ligand, and monitoring the conformational changes of a target induced by ligand binding. A number of studies have proven that 19F-NMR is very powerful in screening fragments and detecting protein conformational changes. In-cell NMR will also play important roles in drug discovery by elucidating protein-ligand interactions in living cells.

show abstract

A Chemical Biology View of Bioactive Small Molecules and a Binder‐Based Approach to Connect Biology to Precision Medicines

Cited by 73 publications

References 34 publications

Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs

Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs

DNA Barcoding a Complete Matrix of Stereoisomeric Small Molecules

A Practical Perspective on the Roles of Solution NMR Spectroscopy in Drug Discovery

Contact Info

Product

Resources

About