CovBinderInPDB: A Structure-Based Covalent Binder Database.

Covalent inhibition has emerged as a promising orthogonal approach for drug discovery, despite the significant challenge in achieving target specificity. To facilitate the structure-based rational design of target-specific covalent modulators, we developed an integrated computational protocol to curate covalent binders from the RCSB Protein Data Bank (PDB). Starting from the macromolecular crystallographic information files (mmCIF) in the PDB archive, covalent bond records, which indicate the side chain modification of amino acid residue by a covalent binder, were collected and cleaned. Then, residue-binder adducts, which are products of chemical reactions between targeted residues and covalent binders, were recovered with the help of the Chemical Component Dictionary in PDB. Finally, several strategies were employed to curate the pre-reaction forms of covalent binders from the adducts. Our curated CovBinderInPDB database contains 7375 covalent modifications in which 2189 unique covalent binders target nine types of amino acid residues (Cys, Lys, Ser, Asp, Glu, His, Met, Thr, and Tyr) from 3555 complex structures of 1170 unique protein chains. This database would set a solid foundation for developing and benchmarking computational strategies for covalent modulator design and is freely accessible at https://yzhang.hpc.nyu.edu/CovBinderInPDB.

Development and validation of a nomogram prognostic model for patients with neuroendocrine tumors of the thymus.

BACKGROUND: The purpose of this study was to analyze the clinical characteristics and prognostic survival of patients with neuroendocrine tumors of the thymus (NETTs), and to develop and validate a nomogram model for predicting the prognosis of patients. METHODS: We conducted a retrospective analysis of patients with neuroendocrine tumors of the thymus in the Surveillance, Epidemiology, and End Results (SEER) database in the United States between 1988 and 2016. Cox scale risk regression analysis, the Kaplan-Meier method and log-rank test were used to carry out the significance test to determine the independent prognostic factors, from which a nomogram for NETTs was established. C-index and calibration curve were used to evaluate the prediction accuracy of the model. External validation of the nomogram was performed using data from our center. RESULTS: A total of 254 patients with NETTs were collected in the SEER database. In the multivariable analysis, T stage, tumor grade, surgery, and chemotherapy were found to be independent factors affecting the prognosis of patients (all P < 0.05). A nomogram model was constructed based on these variables, and its c-index was 0.707 (0.661-0.752). The c-index results showed that the nomogram model had better authentication capability than the eighth edition of the tumor, node, metastasis (TNM) staging system and Masaoka-Koga (MK) staging system. The calibration curve showed that the model could accurately predict patient prognosis. CONCLUSIONS: The study established a nomogram model that predicted the overall survival rate of one-, three- and five-years, and used the survival prediction model to optimize individualized therapy and prognostic follow-up through risk stratification.

Self-assembly of an unprecedented polyoxomolybdate anion [Mo20O66]12- in a giant peanut-like 62-core silver-thiolate nanocluster.

A polyoxometalate-templated silver thiolate nanocluster, [Ag62(S(t)Bu)40(Mo20O66)(Mo6O19)3(CH3CN)2]·(CF3SO3)4 (1), has been isolated, in which a giant peanut-like silver(i)-thiolate cluster [Ag62(S(t)Bu)40](22+) encapsulates an unprecedented [Mo20O66](12-) polyoxoanion core. It opens a new approach for the synthesis of both elusive polyoxometalates and high-nuclearity silver(i)-thiolate nanoclusters.

Mechanistic insights into cobalt(ii/iii)-catalyzed C-H oxidation: a combined theoretical and experimental study.

Cobalt-mediated C-H functionalization has been the subject of extensive interest in synthetic chemistry, but the mechanisms of many of these reactions (such as the cobalt-catalyzed C-H oxidation) are poorly understood. In this paper, possible mechanisms including single electron transfer (SET) and the concerted metalation-deprotonation (CMD) pathways of the CoII/CoIII-catalyzed alkoxylation of C(sp2)-H bonds have been investigated for the first time using the DFT method. CoII(OAc)2 has been employed as an efficient catalyst in our previous experimental study, but the calculated results unexpectedly indicated that the intermolecular SET pathway with CoIII as the actual catalyst might be the most favorable pathway. To support this theoretical prediction, we have explored a series of Cp*CoIII(CO)I2 catalyzed C(sp2)-H bond alkoxylations, extending the application of cobalt-catalyzed functionalization of C-H bonds. Furthermore, kinetic isotope effect (KIE) data, electron paramagnetic resonance (EPR) data, and TEMPO inhibition experiments also support the SET mechanism in both the Co-catalyzed alkoxylation reactions. Thus, this work should support an understanding of the possible mechanisms of the CoII/CoIII-catalyzed C(sp2)-H functionalization, and also provide an example of the rational design of novel catalytic reactions guided by theoretical calculations.

Palladium-catalyzed synthesis of 3-acylated indoles involving oxidative cross-coupling of indoles with α-amino carbonyl compounds.

A new and selective C-N bond oxidative cleavage method to 3-acylated indoles by Pd-catalyzed oxidative cross coupling of indoles with α-amino carbonyl compounds has been developed; moreover, one-pot synthesis of 3-acylated indoles from 2-ethynylanilines and α-amino carbonyl compounds has also been established. Importantly, the products 3-acylated indoles can be used to construct polyheterocyclic compound, which can be employed as efficient probes for Hg(2+) and Fe(3+).