AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Cognitive Performance Following Ingestion of Glucose–Fructose Sweeteners That Impart Different Postprandial Glycaemic Responses: A Randomised Control Trial

We aimed to investigate the isolated effect of glycaemia on cognitive test performance by using beverages sweetened with two different glucose–fructose disaccharides, sucrose and isomaltulose. In a randomised crossover design, 70 healthy adults received a low-glycaemic-index (GI) isomaltulose and sucralose beverage (GI 32) and a high-GI sucrose beverage (GI 65) on two occasions that were separated by two weeks. Following beverage ingestion, declarative memory and immediate word recall were examined at 30, 80 and 130 min. At 140 min, executive function was tested. To confirm that the glycaemic response of the test beverages matched published GI estimates, a subsample (n = 12) of the cognitive testing population (n = 70) underwent glycaemic response testing on different test days. A significantly lower value of mean (95% CI) blood glucose concentration incremental area under the curve (iAUC) was found for isomaltulose, in comparison to the blood glucose concentration iAUC value for sucrose, the difference corresponding to −44 mmol/L∙min (−70, −18), p = 0.003. The mean (95% CI) difference in numbers of correct answers or words recalled between beverages at 30, 80 and 130 min were 0.1 (−0.2, 0.5), −0.3 (−0.8, 0.2) and 0.0 (−0.5, 0.5) for declarative memory, and −0.5 (−1.4, 0.3), 0.4 (−0.4, 1.3) and −0.4 (−1.1, 0.4) for immediate free word recall. At 140 min, the mean difference in the trail-making test between beverages was −0.3 sec (−6.9, 6.3). None of these differences were statistically or clinically significant. In summary, cognitive performance was unaffected by different glycaemic responses to beverages during the postprandial period of 140 min

Butadiyne-Bridged (Porphinato)Zinc(II) Chromophores Assemble into Free-Standing Nanosheets

The molecular engineering of chromophores that enables the controlled and reliable formation of hierarchical solid-state architectures is at the forefront of developing hybrid semiconducting materials. While the rules and principles to assemble monomeric porphyrin-derived building blocks are well established, the aggregation of larger π-conjugated cores that feature electronically coupled porphyrin arrays has been vastly underexplored. In the present contribution, we report the synthesis, spectroscopy, assembly, and solid-state properties of a class of butadiyne-bridged (porphinato)­zinc­(II) dimer chromophores. A spectroscopic investigation unraveled the formation of aggregates in an aqueous medium, leading to the formation of two-dimensional objects that expanded across microscale dimensions. An analysis of the height profile, by atomic force microscopy, indicated that one porphyrin dimer comprises the thickness of the solid-state hierarchical superstructure, which underscores the promise of this approach to engineer solid-state platforms for (opto)­electronic devices. Furthermore, the initiation of noncovalent interactions between building blocks by means of a chemical stimulus (pH) revealed that a nucleation–growth process governs the aggregation of the π-conjugated chromophores in an aqueous medium. This work provides tools to modulate the structure–function relationships of supramolecular architectures equipped with enticing optical properties

How to reprogram the excitonic properties and solid-state morphologies of π-conjugated supramolecular polymers

The development of supramolecular tools to modulate the excitonic properties of non-covalent assemblies paves the way to engineer new classes of semicondcuting materials relevant to flexible electronics. While controlling the assembly pathways of organic chromophores enables the formation of J-like and H-like aggregates, strategies to tailor the excitonic properties of pre-assembled aggregates through post-modification are scarce. In the present contribution, we combine supramolecular chemistry with redox chemistry to modulate the excitonic properties and solid-state morphologies of aggregates built from stacks of water-soluble perylene diimide building blocks. The n-doping of initially formed aggregates in an aqueous medium is shown to produce π-anion stacks for which spectroscopic properties unveil a non-negligible degree of electron-electron interactions. Oxidation of the n-doped intermediates produces metastable aggregates where free exciton bandwidths (ExBW) increase as a function of time. Kinetic data analysis reveals that the dynamic increase of free exciton bandwidth is associated with the formation of superstructures constructed by means of a nucleation-growth mechanism. By designing different redox-assisted assembly pathways, we highlight that the sacrificial electron donor plays a non-innocent role in regulating the structure-function properties of the final superstructures. Furthermore, supramolecular architectures formed via a nucleation-growth mechanism evolve into ribbon-like and fiber-like materials in the solid-state, as characterized by SEM and HRTEM. Through a combination of ground-state electronic absorption spectroscopy, electrochemistry, spectroelectrochemistry, microscopy, and modeling, we show that redox-assisted assembly provides a means to reprogram the structure-function properties of pre-assembled aggregates

Molecular Strategies to Modulate the Electrochemical Properties of P-Type Si(111) Surfaces Covalently Functionalized with Ferrocene and Naphthalene Diimide

The surface coverage and molecular composition of redox-active molecules anchored on conductive surfaces regulate the kinetic and thermodynamic parameters of charge transfer reactions, providing a means to tune the electrochemical properties of hybrid materials. Herein, anchoring strategies and structural properties of redox-active probes, derived from ferrocene (Fc) and naphthalene diimide (NDI), are shown to regulate the electrochemical properties of functionalized p-doped Si(111) surfaces. Covalent functionalization of hydrogen-terminated Si(111) surfaces with Fc and NDI affords redox-active hybrid interfaces characterized through microscopy, spectroscopy, and voltammetry methods. Molecular design and synthetic grafting strategies modulate the electrochemical properties of the Fc-functionalized Si surfaces with a much higher (ca. 25 times) surface coverage (1.25 × 10 mol cm ) for one-step photografting compared to divergent synthetic routes. Interestingly, the thermal grafting of an alkadiyne followed by "click" reaction with ferrocenyl-azide leads to one of the highest surface coverages (9.97 × 10 mol cm ) of organo-iron reported and a significant anodic shift of the half-potential (>350 mV) compared to photografting methods. Similar experiments with NDI units exhibited electrochemical properties that diverge from those recorded for NDI in solution. The results presented herein offer access to novel redox-active Si interfaces that evidence tunable electrochemical properties of potential interest for microelectronic applications

Leveraging the Assembly of a Rylene Dye to Tune the Semiconducting Properties of Functionalized n‑Type, Hybrid Si Interfaces

The functionalization of silicon electrodes with π-conjugated chromophores opens new avenues to engineer hybrid semiconducting interfaces relevant to information storage and processing. Notably, molecularly dissolved π-conjugated units, such as ferrocene derivatives, are traditionally exploited as building blocks to construct well-defined interfaces that establish electrochemically addressable platforms with which to investigate electron transfer properties and charge storage capabilities. In contrast, planar π-conjugated building blocks such as naphthalene diimide (NDI) cores enable the formation of solvated aggregates equipped with emergent electronic structures not manifested by the parent, molecularly dissolved building blocks. To interrogate the extent to which the aggregated states of π-conjugated chromophores can be leveraged to regulate the n-type semiconducting properties of functionalized electrodes, we have devised an amphiphilic rylene core (NDI) that demonstrates a non-negligible degree of aggregation in an aqueous medium. Characterization of the electronic structures of the NDI-derived aggregates using a combination of electrochemistry, reductive titration experiments, and spectroelectrochemistry unveils the existence of π-anion stacks, the formation of which is contingent on the initial concentration of NDI building blocks. We show that grafting n-doped NDI aggregates on silicon electrode precursors equipped with a high density of anchoring groups by means of “click” reaction enables the formation of the hybrid Si-NDI electrode (Si-NDI-15@1) that facilitates electron injection by more than 400 mV when compared to Si interfaces constructed from molecularly dissolved NDI units. Furthermore, the engineering of a Si precursor surface characterized by a low density of anchoring groups provides additional proof to highlight that the potentiometric properties recorded for Si-NDI-15@1 originate from NDI units, evidencing a non-negligible degree of aggregation. The present work delivers tools to manipulate the potentiometric properties of functionalized electrodes by leveraging on the electronic structures of aggregated, π-conjugated precursors

A Molecular Strategy to Lock‐in the Conformation of a Perylene Bisimide‐Derived Supramolecular Polymer

Locking‐in the conformation of supramolecular assemblies provides a new avenue to regulate the (opto)electronic properties of robust nanoscale objects. In the present contribution, we show that the covalent tethering of a perylene bisimide (PBI)‐derived supramolecular polymer with a molecular locker enables the formation of a locked superstructure equipped with emergent structure–function relationships. Experiments that exploit variable‐temperature ground‐state electronic absorption spectroscopy unambiguously demonstrate that the excitonic coupling between nearest neighboring units in the tethered superstructure is preserved at a temperature (371 K) where the pristine, non‐covalent assembly exists exclusively in a molecularly dissolved state. A close examination of the solid‐state morphologies reveals that the locked superstructure engenders the formation of hierarchical 1D materials which are not achievable by unlocked assemblies. To complement these structural attributes, we further demonstrate that covalently tethering a supramolecular polymer built from PBI subunits enables the emergence of electronic properties not evidenced in non‐covalent assemblies. Using cyclic voltammetry experiments, the elucidation of the potentiometric properties of the locked superstructure reveals a 100‐mV stabilization of the conduction band energy when compared to that recorded for the non‐covalent assembly. Locking‐in the conformation of supramolecular polymers delivers a new class of robust, π‐conjugated nanoscale objects. Spectroscopic and electrochemical measurements elucidate the unique optoelectronic properties of these semiconducting superstructures