Accurately predicting the binding affinities of small organic molecules to biological macro-molecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macro-molecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host-guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host-guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from 10 participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host-guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host-guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host-guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states) may be required to further enhance predictive accuracy.

The ability to accurately predict the binding affinities of small organic molecules to biological 15 macromolecules would greatly accelerate drug discovery by reducing the number of compounds that must 16 be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the 17 accuracy of current quantitative physical and empirical modeling approaches to affinity prediction against 18 binding data to biological macromolecules is frustrated by several challenges, such as slow conformational 19 dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several 20 SAMPL blind challenge exercises, host-guest systems have emerged as a practical and effective way to 21 circumvent these challenges in assessing the predictive performance of current-generation quantitative 22 modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present 23 an overview of the SAMPL6 host-guest binding affinity prediction challenge, which featured three supramolec-24 ular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), 25 along with 21 small organic guest molecules. A total of 119 entries were received from 10 participating 26 groups employing a variety of methods that spanned electronic structure and movable type calculations 27 in implicit solvent to alchemical and potential of mean force strategies using empirical force fields and 28 explicit solvent models. While empirical models tended to obtain better performance, it was not possible 29 to identify a single approach consistently providing superior predictions across all host-guest systems and 30 statistical metrics, and the accuracy of the methodologies generally displayed a substantial dependence on 31 the systems considered, arguing for the importance of considering a diverse set of hosts in blind evaluations. 32 Several entries exploited previous experimental measurements of similar host-guest systems in an effort 33 to improve their physical-based predictions via some manner of rudimentary machine learning; while this 34 strategy succeeded in reducing systematic errors, it was not able to generated a corresponding improvement 35 of correlation statistics. Comparison to previous rounds of the host-guest binding free energy challenge 36 highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA 37 systems, but a surprising lack of improvement in root mean square error over the past several challenge 38 rounds. The data suggests that further refinement of force field parameters and improved treatment of 39 chemical effects (e.g., buffer salt conditions, protonation states) may be required to continue to enhance 40 predictive accuracy. 41 42 1 of 35 Preprint ahead of submission -July 18, 2018 48 Assessment of how much of this inaccuracy can be attributed to fundamental limitations of the force 49 field in accurately modeling energetics ...

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Inclusion of a second nitrogen atom in the aromatic core of phosphorus‐nitrogen (PN) heterocycles results in unexpected tautomerization to a nonaromatic form. This tautomerization, initially observed in the solid state through X‐ray crystallography, is also explained by computational analysis. We prepared an electron deficient analogue (2 e) with a fluorine on the pyridine ring and showed that the weakly basic pyridine resisted tautomerization, providing key insights to why the transformation occurs. To study the difference in solution vs. solid‐state heterocycles, alkylated analogues that lock in the quinoidal tautomer were synthesized and their different 1H NMR and UV/Vis spectra studied. Ultimately, we determined that all heterocycles are the aromatic tautomer in solution and all but 2 e switch to the quinoidal tautomer in the solid state. Better understanding of this transformation and under what circumstances it occurs suggest future use in a switchable on/off hydrogen‐bond‐directed receptor that can be tuned for complementary hydrogen bonding.

Lawesson's reagent is one of the most common thionating reagents that has found use for several decades on a variety of carbonyl systems. Herein, we report the transformation of the 2‐λ5‐phosphaquinolin‐2‐one structure to its respective 2‐λ5‐phosphaquinolin‐2‐thione derivative. Solution‐state characterization of both P−OPh and P−Ph thio analogues, as well as solid‐state structures for the latter system, are reported.

The phosphaquinolinone scaffold has been previously studied as a modular core for a variety of fluorescent species where use of substituent effects has focused on increasing or decreasing electron density in the core rings. We now report the synthesis and analysis of several pyridinecontaining phosphaquinolinone species exhibiting notable linear conjugation from the aryl-substituent to electron-withdrawing pyridyl nitrogen. Varying the nature of the aryl substituent from electron-withdrawing to electron-donating leads to the generation of an internal charge-transfer (ICT) band in the absorbance spectrum, which becomes the dominant absorbance in terms of intensity in the most electron-rich -NMe 2 example. This heterocycle exhibits improved photophysical properties compared to others in the set including high quantum yield and considerably redshifted emission. The enhanced ICT can be observed in the Xray data where a rare example of molecule co-planarity is observed. Computational data show increased localization of negative charge on the pyridyl nitrogen as the electrondonating character of the aryl-substituent increases.