The modeling of the conformational properties of conjugated polymers entails a unique challenge for classical force fields. Conjugation imposes strong constraints upon bond rotation. Planar configurations are favored, but the concomitantly shortened bond lengths result in moieties being brought into closer proximity than usual. The ensuing steric repulsions are particularly severe in the presence of side chains, straining angles, and stretching bonds to a degree infrequently found in nonconjugated systems. We herein demonstrate the resulting inaccuracies by comparing the LMP2-calculated inter-ring torsion potentials for a series of substituted stilbenes and bithiophenes to those calculated using standard classical force fields. We then implement adjustments to the OPLS-2005 force field in order to improve its ability to model such systems. Finally, we show the impact of these changes on the dihedral angle distributions, persistence lengths, and conjugation length distributions observed during molecular dynamics simulations of poly[2-methoxy-5-(2'-ethylhexyloxy)-p-phenylene vinylene] (MEH-PPV) and poly 3-hexylthiophene (P3HT), two of the most widely used conjugated polymers.

Herein we report the first fully quantum mechanical study of enantioselectivity for a large dataset. We show that transition state modeling at the UB3LYP-DFT/6-31G* level of theory can accurately model enantioselectivity for various dioxirane-catalyzed asymmetric epoxidations. All the synthetically useful high selectivities are successfully "predicted" by this method. Our results hint at the utility of this method to further model other asymmetric reactions and facilitate the discovery process for the experimental organic chemist. Our work suggests the possibility of using computational methods not simply to explain organic phenomena, but also to predict them quantitatively.

A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction of protein–ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling is among the most suitable approaches to achieve accurate binding free energy predictions, due to the rigorous statistical framework of the methodology, correct representation of the energetics, and thorough treatment of the important degrees of freedom in the system (including explicit waters). Recent advances in sampling methods and force fields coupled with vast increases in computational resources have made FEP a viable technology to drive hit-to-lead and lead optimization, allowing for more efficient cycles of medicinal chemistry and the possibility to explore much larger chemical spaces. However, previous FEP applications have focused on systems with high-resolution crystal structures of the target as starting points—something that is not always available in drug discovery projects. As such, the ability to apply FEP on homology models would greatly expand the domain of applicability of FEP in drug discovery. In this work we apply a particular implementation of FEP, called FEP+, on congeneric ligand series binding to four diverse targets: a kinase (Tyk2), an epigenetic bromodomain (BRD4), a transmembrane GPCR (A2A), and a protein–protein interaction interface (BCL-2 family protein MCL-1). We apply FEP+ using both crystal structures and homology models as starting points and find that the performance using homology models is generally on a par with the results when using crystal structures. The robustness of the calculations to structural variations in the input models can likely be attributed to the conformational sampling in the molecular dynamics simulations, which allows the modeled receptor to adapt to the “real” conformation for each ligand in the series. This work exemplifies the advantages of using all-atom simulation methods with full system flexibility and offers promise for the general application of FEP to homology models, although additional validation studies should be performed to further understand the limitations of the method and the scenarios where FEP will work best.

Background: The calcium-activated chloride channel ANO1 is highly expressed in cancer.Results: Inhibition of ANO1 activity alone is not sufficient to inhibit cancer cell proliferation, suggesting a novel function of ANO1 protein in cancer.Conclusion: The ANO1 inhibitor CaCCinh-A01 inhibits cancer cell proliferation by facilitating degradation of ANO1.Significance: Our results may provide a new targeting approach for antitumor therapy in ANO1-amplified cancers.

The stoichiometric reduction of N-carbophenoxypyridinium tetraphenylborate (6) by CpRu(P-P)H (Cp = η 5 -cyclopentadienyl; P-P = dppe, 1,2-bis(diphenylphosphino)ethane or dppf, 1,1′-bis (diphenylphosphino)ferrocene) and Cp*Ru(P-P)H (Cp* = η 5 -pentamethylcyclopentadienyl; P-P = dppe) gives mixtures of 1,2-and 1,4-dihydropyridines. The stoichiometric reduction of 6 by Cp*Ru (dppf)H (5) gives only the 1,4-dihydropyridine, and 5 catalyzes the exclusive formation of the 1,4-dihydropyridine from 6, H 2 , and 2,2,6,6-tetramethylpiperidine. In the stoichiometric reductions, the ratio of 1,4 to 1,2 product increases as the Ru hydrides become better one-electron reductants, suggesting that the 1,4 product arises from a two-step (e − /H•) hydride transfer. Calculations at the UB3LYP/6-311++G(3df,3pd)//UB3LYP/6-31G* level support this hypothesis, indicating that the spin density in the N-carbophenoxypyridinium radical (13) resides primarily at C4, while the positive charge in 6 resides primarily at C2 and C6. The isomeric dihydropyridines thus result from the operation of different mechanisms: the 1,2 product from a single-step H − transfer and the 1,4 product from a two-step (e − /H•) transfer.