Molecule VI: Sulfonimide or Sulfonamide?

The tautomerism of molecule <b>VI</b>, a benchmark system for crystal structure predictions, has been investigated by the use of computational chemistry. Ab initio and density functional calculations including dispersion corrections show that monomers of molecule <b>VI</b> strongly (11 kcal mol^–1) prefer to exist as sulfonamide tautomer, while remarkably the equilibrium is shifted toward sulfonimide tautomers in larger aggregates due to formation of stronger hydrogen bonds for the imide tautomer

Toward Accurate Post-Born–Oppenheimer Molecular Simulations on Quantum Computers: An Adaptive Variational Eigensolver with Nuclear-Electronic Frozen Natural Orbitals

Nuclear quantum effects such as zero-point energy and hydrogen tunneling play a central role in many biological and chemical processes. The nuclear-electronic orbital (NEO) approach captures these effects by treating selected nuclei quantum mechanically on the same footing as electrons. On classical computers, the resources required for an exact solution of NEO-based models grow exponentially with system size. By contrast, quantum computers offer a means of solving this problem with polynomial scaling. However, due to the limitations of current quantum devices, NEO simulations are confined to the smallest systems described by minimal basis sets, whereas realistic simulations beyond the Born–Oppenheimer approximation require more sophisticated basis sets. For this purpose, we herein extend a hardware-efficient ADAPT-VQE method to the NEO framework in the frozen natural orbital (FNO) basis. We demonstrate on H2 and D2 molecules that the NEO-FNO-ADAPT-VQE method reduces the CNOT count by several orders of magnitude relative to the NEO unitary coupled cluster method with singles and doubles while maintaining the desired accuracy. This extreme reduction in the CNOT gate count is sufficient to permit practical computations employing the NEO methodan important step toward accurate simulations involving nonclassical nuclei and non-Born–Oppenheimer effects on near-term quantum devices. We further show that the method can capture isotope effects, and we demonstrate that inclusion of correlation energy systematically improves the prediction of difference in the zero-point energy (ΔZPE) between isotopes

Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation

G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, <b>2</b>, into a development candidate, <b>42</b>. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism