Article
Chemistry, Multidisciplinary
Xiaowei Li, Tania M. Palhano Zanela, Eric S. Underbakke, Yan Zhao
Summary: This study introduces a method to precisely manipulate kinase phosphorylation using synthetic receptors, achieving selective phosphorylation of peptides. The inhibition can block the phosphorylation of specific sites while allowing phosphorylation at other sites, and the receptors can work individually or together to protect substrate sequences.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Medicinal
Ying Yang, Lei Zhang, Jinying Tian, Fei Ye, Zhiyan Xiao
Summary: A hierarchical virtual screening identified four potential PTP1B inhibitors with distinct structures, among which H3 and H9 showed selectivity to PTP1B. Key residues responsible for potent allosteric inhibition and excellent PTP selectivity were identified through molecular dynamics simulations and MM-GBSA calculations, aiding future molecular design of PTP1B allosteric inhibitors.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Chemistry, Multidisciplinary
Chao Zhou, Qi-Chao Gan, Tai-Ping Zhou, Tao Lei, Chen Ye, Xiao-Jun He, Bin Chen, Heng Lu, Qian Wan, Rong-Zhen Liao, Chen-Ho Tung, Li-Zhu Wu
Summary: This study reports the first regioselective heteroarylation of indole through a radical-radical cross-coupling using visible-light irradiation. Spectroscopic and computational studies show that the hydrogen-bonding interaction between an organic base and its conjugated acid plays a crucial role in determining the reaction pathway, resulting in regioselective formation of C-3 and N-1 heteroarylation of indoles. This methodology has great potential in large-scale synthesis and late-stage derivatization of bioactive compounds.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Multidisciplinary Sciences
Jianxin Liu, Jiayi Tian, Christopher Perry, April L. Lukowski, Tzanko Doukov, Alison R. H. Narayan, Jennifer Bridwell-Rabb
Summary: In this study, the crystal structures of two Rieske oxygenases, SxtT and GxtA, were determined with their native substrates. The authors also identified key amino acid residues that determine the substrate specificity and site selectivity of these enzymes. These findings provide valuable insights for the engineering of Rieske oxygenases.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Organic
Niels R. M. Reintjens, Martin D. Witte, Adriaan J. Minnaard
Summary: Thioglycosides or S-linked-glycosides are important glycomimetics that can be synthesized by glycosylating deoxythio sugar acceptors. A carbonyl group formed by site-selective oxidation of unprotected saccharides can be converted into a thiol moiety, allowing for the preparation of deoxythio sugars through S(N)1 substitution reactions. The combination of these deoxythio sugars with protecting group-free glycosylation of glycosyl fluorides enables a protecting group-free synthesis of thioglycosides.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Cindy Rodriguez, Samantha Delaney, Joni Sebastiano, Samantha M. M. Sarrett, Mike A. A. Cornejo, Sarah Thau, Meena M. M. Hosny, Brian M. M. Zeglis
Summary: We characterized and evaluated a novel Zr-89-labeled radioimmunoconjugate using a site-selective bioconjugation strategy. The radioimmunoconjugate was synthesized by modifying an A33 antigen-targeting antibody with the chelator desferrioxamine (DFO) and subsequently radiolabeling with [Zr-89]Zr4+. It exhibited excellent in vivo behavior in murine models of human colorectal carcinoma.
Article
Biology
Jeffrey R. McArthur, Jierong Wen, Andrew Hung, Rocio K. Finol-Urdaneta, David J. Adams, Henry M. Colecraft
Summary: The spider venom peptide inhibitor Pn3a has been identified as a subtype-selective inhibitor of the Ca(V)3.3 T-type calcium channel. It modifies the gating of Ca(V)3.3 and decreases its currents by shifting the voltage dependence of activation. This study expands our understanding of T-type calcium channel pharmacology and highlights the potential use of Pn3a as a molecular tool in studying the physiological roles of Ca(V)3.3 channels.
Article
Chemistry, Multidisciplinary
Lisa Chen, Mona Arnold, Remi Blinder, Fedor Jelezko, Alexander J. C. Kuehne
Summary: Derivatives of the stable, luminescent TTM radical with mixed halides can be obtained through simple Friedel-Crafts alkylation, showing higher stability and site-specific reactivity. These radicals serve as powerful building blocks for the synthesis of stable luminescent molecules.
Article
Multidisciplinary Sciences
Madeleine R. Wilcox, Aparna Nigam, Nathan G. Glasgow, Chamali Narangoda, Matthew B. Phillips, Dhilon S. Patel, Samaneh Mesbahi-Vasey, Andreea L. Turcu, Santiago Vazquez, Maria G. Kurnikova, Jon W. Johnson
Summary: The study reveals that NMDA receptor channel blockers can access their binding site through two routes, providing insights into their mechanisms of action. This finding is important for understanding the neural signal transmission.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Kamaleddin H. M. E. Tehrani, Nicola Wade, Vida Mashayekhi, Nora C. Bruchle, Willem Jespers, Koen Voskuil, Diego Pesce, Matthijs J. van Haren, Gerard J. P. van Westen, Nathaniel Martin
Summary: The novel cephalosporin prodrugs designed to inhibit metallo-beta-lactamases have shown potential, especially the thiomandelic acid conjugate (8). Conjugate 8 not only effectively inhibits IMP-type MBLs, but also significantly reduces the minimum inhibitory concentration of meropenem against IMP-producing bacteria. These prodrugs act as slowly turned-over substrates to inhibit IMP-type MBLs, with the phenyl and carboxyl moieties of crucial importance for potency.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Niu Zhang, Zhicheng Zuo
Summary: The discovery of small-molecule Cas9 inhibitors provides a feasible approach to regulate CRISPR-Cas9 activity. Through computational analysis, a ligand binding site was identified within the carboxyl-terminal domain (CTD) of Cas9, which plays a role in recognizing the protospacer adjacent motif (PAM). Binding of the inhibitor BRD0539 induced structural rearrangements in the CTD, leading to the inhibition of Cas9 function. This study offers insights into the development of safer CRISPR-Cas9 technologies through improving existing ligands and discovering novel small-molecule brakes.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Xuesen Qi, Guozhen Li, Jiahai Liu, Linkai Mou, Yusheng Zhang, Shilin Guo, Xiangyu Chen, Wenxing Li
Summary: In this study, the binding selectivity mechanism of RP-6306 towards PKMYT1 was uncovered using molecular docking, molecular dynamics simulations, and free energy calculations. The results clarified the binding specificity of RP-6306 reported in previous bioassays and showed that the selectivity largely derived from protein-ligand electrostatic interactions. The critical factor responsible for the binding selectivity was identified as the non-conserved gatekeeper residue Thr187 in PKMYT1.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Sanket J. Mishra, Weiya Liu, Kristin Beebe, Monimoy Banerjee, Caitlin N. Kent, Vitumbiko Munthali, John Koren, John A. Taylor, Leonard M. Neckers, Jeffrey Holzbeierlein, Brian S. J. Blagg
Summary: Hsp90 proteins play a crucial role in cancer progression, and inhibiting their activity may be beneficial for cancer treatment. Current Hsp90 inhibitors target all isoforms, potentially leading to adverse effects. Utilizing Hsp90 beta-selective inhibitors as a new approach for cancer therapy holds promise in reducing side effects.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Carlos Moreno-Yruela, Michael Baek, Adela-Eugenie Vrsanova, Clemens Schulte, Hans M. Maric, Christian A. Olsen
Summary: Researchers successfully captured HDAC using hydroxamic acid-modified microarray technology, providing insights into their substrate specificity and facilitating inhibitor development.
NATURE COMMUNICATIONS
(2021)
Article
Pharmacology & Pharmacy
Matyas C. Foldi, Krisztina Pesti, Katalin Zboray, Adam V. Toth, Tamas Hegedus, Andras Malnasi-Csizmadia, Peter Lukacs, Arpad Mike
Summary: The research found that riluzole mainly acts on Nav1.4 sodium channels by non-blocking modulation, selectively inhibiting pathological activity. Riluzole is identified as the prototype of a new class of sodium channel inhibitors, expected to selectively prevent hyperexcitability with minimal impact on normal cell activity.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)