Fraser Hof

Mixed-host co-assemblies formed by mixing high-affinity, promiscuous sulfo-pillar[ n ]arenes and a DimerDye host give rise to emergent sensing behaviors: information richness, ternary complex formation, and increased sensitivity.

The development and SAR of cell-active small-molecule CBX7 inhibitors is reported.

The binding of complex guests with supramolecular hosts is difficult to model. A dataset of 38 calixarene hosts and 8 peptide guests was evaluated with five ML models of varying complexity; a graph neural network displayed the best performance.

The availability of large datasets such as the Protein DataBank and ChEMBL have allowed for rapid progress in developing machine learning tools for predicting the biological activity of organic small molecules. The binding between supramolecular hosts and their desired guests are governed by the same forces that drive protein-small molecule interactions, and yet this field has seen dramatically less application of machine learning. In this contribution, we demonstrate that the production of easily diversified building blocks can allow a single laboratory to generate a dataset that is sufficient to engage with modern machine learning approaches. A range of methods were evaluated against our single-laboratory dataset, with a graph neural network featuring an attention mechanism providing meaningful performance in this data-sparse arena.

Host-based sensors that offer cross-reactivity to analytes can be valuable tools in the detection and differentiation of biologically relevant molecules.

Host-based sensors that offer cross-reactivity to analytes can be valuable tools in the detection and differentiation of biologically relevant molecules. This Feature Article provides a foundational background in developing macrocylic host-based systems that harness chemical complexity to achieve sensing in biologically relevant solutions. We highlight our own contributions along with select examples from others, covering noncovalent self-assemblies, salt tolerant synthetic designs, and current multicomponent systems approaches to host-based sensing and differentation. We emphasize our personal perspective on building complex systems, as an evolving strategy to obtaining emergent information-rich outputs that surpass the performance of conventional host-based sensor pairs. These recent developments are at the frontier of the field, involving more challenging sensing tasks, including the detection and identification of highly similar analytes, biomacromolecules, and complex mixtures.

Herein, we report the synthesis of extended sulfo-pillar[6]arenes (sP6), a new host class with a pedigree in salt tolerance and ultrahigh binding affinity toward multiple drug classes. The parent sulfo-pillar[6]arene is a high-affinity host with the potential to act as a supramolecular reversal agent. However, it lacks synthetic diversification of the core scaffold. The new extended sulfo-pillar[6]arenes have either a monodirectional (A1sP6) or bidirectional (A1A2sP6) extension of the hydrophobic cavity. This new functionality enables more noncovalent interactions and strong affinity toward guests, which we demonstrate using the direct oral anticoagulants (DOACs) dabigatran, betrixaban, and edoxaban. DOACs are highly prescribed therapeutics that are underexplored in host-guest chemistry. These agents prevent the formation of blood clots and are prime targets for supramolecular sequestration. This functionalization also introduces new fluorescent properties to the sulfo-pillar[6]arene family via an incorporated p-terphenyl (A1A2sP6). We show that these new hosts have ultrahigh affinity toward dabigatran (K_d = 27 nM, A1A2sP6) in salty solutions and that the A1A2sP6 analogue can bind betrixaban in bovine plasma with a physiologically relevant K_d (7 μM).

Here we report a systems chemistry oriented approach for developing information-rich mixed host chemosensors. We show that co-assembling macrocyclic hosts from different classes, DimerDye sulfonatocalix[4]arenes and cucurbit[n]urils, effectively increases the scope of analyte binding interactions and therefore, sensory outputs. This simple dynamic strategy exploits cross-reactive noncovalent host–host complexation interactions while integrating a reporter dye, thereby producing emergent photophysical responses when an analyte interacts with either host. We first demonstrate the advantages of mixed host co-assembled chemosensors through an increased detection range of hydrophobic, cationic, neutral, and anionic drugs. We then implement mixed host sensors in an array-based platform for the differentiation of illicit drugs, including cannabinoids, benzodiazepine analogs, opiates, anesthetics, amphetamine, and common adulterating substances. Finally, the potential of this approach is applied to profiling real-world multi-component illicit street drug samples, proving to be more effective than classical sensor arrays.

Herein we report the synthesis of extended sulfo-pillar[6]arenes, a new supramolecular host class with a pedigree in salt tolerance and ultra-high binding affinity towards multiple drug classes. The parent sulfo-pillar[6]arene (sP6) is a high affinity host with the potential to act as a supramolecular reversal agent. However, it lacks synthetic diversification of the core scaffold. The new extended sulfo-pillar[6]arenes have either a mono-directional (A1sP6) or bi-directional (A1A2sP6) extension of the hydrophobic cavity. This new functionality enables more non-covalent interactions and strong affinity towards guests, which we demonstrate using the direct oral anticoagulants (DOACs) dabigatran, betrixaban, and edoxaban. DOACs are highly prescribed therapeutics that are underexplored in host-guest chemistry. These agents prevent the formation of blood clots and reversing their action during emergencies is paramount. We show that the new hosts have ultra-high affinity to-wards dabigatran (Kd = 27 nM, A1A2sP6) in salty solutions. Their increased functionality resulted in a 6- and 2.5-fold in-crease in affinity towards betrixaban (Kd = 230 nM, A1A2sP6) and edoxaban (Kd = 800 nM, A1sP6), relative to the unfunctionalized sulfo-pillar[6]arene.