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Accurate structural feature characterization of cyclic peptides (CPs), especially those with less than 10 residues and cis -peptide bonds, is challenging but important for the rational design of bioactive peptides. In this study, we performed high-temperature molecular dynamics (high-T MD) simulations on 250 CPs with random sequences and applied the point-adaptive k-nearest neighbors (PAk) method to estimate the free energies of millions of sampled conformations. Using this data set, we trained a SchNet-based deep learning model, termed CPconf_score, to predict the conformational free energies of CPs. We tested CPconf_score to identify near-native conformations from MD-sampled conformations of 50 CPs from the Cambridge Structural Database. Our method achieved accurate predictions for 41 out of 50 CPs with a backbone RMSD of less than 1.0 Å compared to crystal structures. In comparison, other advanced CP structure prediction tools, such as HighFold and Rosetta, successfully predicted 12 and 19 CPs, respectively.

The combination of histone deacetylase inhibitor and BRAF inhibitor (BRAFi) has been shown to enhance the antineoplastic effect and reduce the progress of BRAFi resistance. In this study, a series of (thiazol-5-yl)pyrimidin-2-yl)amino)- N -hydroxyalkanamide derivatives were designed and synthesized as novel dual inhibitors of BRAF and HDACs using a pharmacophore hybrid strategy. In particular, compound 14b possessed potent activities against BRAF, HDAC1, and HDAC6 enzymes. It potently suppressed the proliferation of HT-29 cells harboring BRAF V600E mutation as well as HCT116 cells with wild-type BRAF. The dual inhibition against BRAF and HDAC downstream proteins was validated in both cells. Collectively, the results support 14b as a promising lead molecule for further development and a useful tool for studying the effects of BRAF/HDAC dual inhibitors., Competing Interests: Author HC is employed by XtalPi Inc (Shenzhen Jingtai Technology Co., Ltd). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Huang, Cheng, Xu, Qi, Dai, Yang, Tu, Peng and Zhang.)

A novel formal cross-coupling of aryl methyl sulfones and alcohols affording alkyl aryl ethers via an S RN 1 pathway is developed. Two marketed antitubercular drugs were efficiently prepared employing this approach as the key step. A dimsyl-anion initiated radical chain process was revealed as the major pathway. DFT calculations indicate that the formation of a radical anion via nucleophilic addition of alkoxide to the aryl radical is the key step in determining the observed chemoselectivity.

In this study, estimates of the growth rate of new infections, based on the growth rate of new laboratory-confirmed cases, were used to provide a statistical basis for in-depth research into the epidemiological patterns of H7N9 epidemics. The incubation period, interval from onset to laboratory confirmation, and confirmation time for all laboratory-confirmed cases of H7N9 avian influenza in Mainland China, occurring between January 2013 and June 2017, were used as the statistical data. Stochastic processes theory and maximum likelihood were used to calculate the growth rate of new infections. Time-series analysis was then performed to assess correlations between the time series of new infections and new laboratory-confirmed cases. The rate of new infections showed significant seasonal fluctuation. Laboratory confirmation was delayed by a period of time longer than that of the infection (average delay, 13 days; standard deviation, 6.8 days). At the lags of -7.5 and -15 days, respectively, the time-series of new infections and new confirmed cases were significantly correlated; the cross correlation coefficients (CCFs) were 0.61 and 0.16, respectively. The temporal distribution characteristics of new infections and new laboratory-confirmed cases were similar and strongly correlated.