Identification and semisynthesis of (-)-anisomelic acid as oral agent against SARS-CoV-2 in mice.

(-)-Anisomelic acid, isolated from (L.) Kuntze (Labiatae) leaves, is a macrocyclic cembranolide with a -fused α-methylene-γ-lactone motif. Anisomelic acid effectively inhibits SARS-CoV-2 replication and viral-induced cytopathic effects with an EC of 1.

Identification of DNA aptamers that specifically targets EBV nasopharyngeal carcinoma via binding with EphA2/CD98hc complex.

Nasopharyngeal carcinoma (NPC) is one of the Epstein-Barr virus (EBV)-associated malignancies and has a distinct geographical distribution. The high mortality rates of NPC patients with advanced and recurrent disease highlight the urgent need for biomarkers for early diagnosis and effective treatments. In this study, we developed DNA aptamers that specifically bind to EBV positive NPC cells by the Cell-SELEX procedure.

Targeting Extracellular Cyclophilin A via an Albumin-Binding Cyclosporine A Analogue.

An albumin-binding CsA analogue 4MCsA was achieved by attachment of a thiol-reactive maleimide group at the side-chain of P4 position of CsA derivative. 4MCsA was semi-synthesized from CsA, and the cell-impermeability of albumin-4MCsA was detected by mass spectrometry and a competitive flow cytometry. 4MCsA exhibits inhibition of chemotaxis activity and inflammation by targeting extracellular CypA without immunosuppressive effect and cellular toxicity.

Comparative pharmacokinetic profile of cyclosporine (CsA) with a decapeptide and a linear analogue.

The synthesis and in vivo pharmacokinetic profile of an analogue of cyclosporine is disclosed. An acyclic congener was also profiled in in vitro assays to compare cell permeability. The compounds possess similar calculated and measured molecular descriptors however have different behaviors in an RRCK assay to assess cell permeability.

Structure-based design of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3β inhibitors to activate Wnt/β-catenin pathway.

Deregulation of Wnt/β-catenin pathway is closely related to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), and glycogen synthase kinase 3β (GSK-3β), the central negative regulator of Wnt pathway, is regarded as an important target for these diseases. Here, we report a series of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3β inhibitors by rational-design and synthesis, which show high selectivity against GSK-3β over Cyclin-dependent kinase 2 (CDK2), and significantly activate the cellular Wnt/β-catenin pathway. The structure-activity relationship of these GSK-3β inhibitors was also explored by in silico molecular docking.

Crystal structure of the death effector domains of caspase-8.

Caspase-8 is a key mediator in various biological processes such as apoptosis, necroptosis, inflammation, T/B cells activation, and cell motility. Caspase-8 is characterized by the N-terminal tandem death effector domains (DEDs) and the C-terminal catalytic protease domain. The DEDs mediate diverse functions of caspase-8 through homotypic interactions of the DEDs between caspase-8 and its partner proteins.

Crystal structure of the polo-box domain of polo-like kinase 2.

Polo-like kinase 2 (PLK2) is a crucial regulator in cell cycle progression, DNA damage response, and neuronal activity. PLK2 is characterized by the conserved N-terminal kinase domain and the unique C-terminal polo-box domain (PBD). The PBD mediates diverse functions of PLK2 by binding phosphorylated Ser-pSer/pThr motifs of its substrates.

Oxygen insertion of o-quinone under catalytic hydrogenation conditions.

An oxygen-insertion reaction that transforms an o-quinone and a conjugated α-diketone substrate into an anhydride product or derivative under catalytic hydrogenation conditions is reported. The experiments and computations indicate that the oxygen insertion proceeds via a radical mechanism mediated by an acetoxyl radical.

Theoretical studies on the mechanism and stereoselectivity of Rh(Phebox)-catalyzed asymmetric reductive aldol reaction.

Density functional theory calculations (B3LYP) have been carried out to understand the mechanism and stereochemistry of an asymmetric reductive aldol reaction of benzaldehyde and tert-butyl acrylate with hydrosilanes catalyzed by Rh(Phebox-ip)(OAc)(2)(OH(2)). According to the calculations, the reaction proceeds via five steps: (1) oxidative addition of hydrosilane, (2) hydride migration to carbon-carbon double bond of tert-butyl acrylate, which determines the chirality at C2, (3) tautomerization from rhodium bound C-enolate to rhodium bound O-enolate, (4) intramolecular aldol reaction, which determines the chirality at C3 and consequently the anti/syn-selectivity, and (5) reductive elimination to release aldol product. The hydride migration is the rate-determining step with a calculated activation energy of 23.

Understanding the binding mode and function of BMS-488043 against HIV-1 viral entry.

A recently discovered small-molecule inhibitor, BMS-488043 (BMS-488), for the invasion of Human immunodeficiency virus Type 1 (HIV-1), shows a high activity against the entry of diversified HIV-1. Docking and molecular dynamic studies have been carried out to understand the binding mode of BMS-488 to gp120 as well as the effect of the small molecule on the conformational change of gp120 induced by CD4 binding. The results indicate that BMS-488 can accommodate in the CD4 binding pocket and interfere the CD4 binding in a noncompetitive mode.

Intermediate-assisted multifunctional catalysis in the conversion of flavin to 5,6-dimethylbenzimidazole by BluB: a density functional theory study.

BluB is a distinct flavin destructase that catalyzes a complex oxygen-dependent conversion of reduced flavin mononucleotide (FMNH(2)) to form 5,6-dimethylbenzimidazole (DMB), the lower ligand of vitamin B(12). The catalyzed mechanism remains a challenge due to the discrepancy between the complexity of the conversion and the relative simplicity of the active site of BluB. In this study, we have explored the detailed conversion mechanism by using the hybrid density functional method B3LYP on an active site model of BluB consisting of 144 atoms.

A theoretical study on the catalytic mechanism of Mus musculus adenosine deaminase.

The catalytic mechanism of Mus musculus adenosine deaminase (ADA) has been studied by quantum mechanics and two-layered ONIOM calculations. Our calculations show that the previously proposed mechanism, involving His238 as the general base to activate the Zn-bound water, has a high activation barrier of about 28 kcal/mol at the proposed rate-determining nucleophilic addition step, and the corresponding calculated kinetic isotope effects are significantly different from the recent experimental observations. We propose a revised mechanism based on calculations, in which Glu217 serves as the general base to abstract the proton of the Zn-bound water, and the protonated Glu217 then activates the substrate for the subsequent nucleophilic addition.

Understanding of the bridging sheet formation of HIV-1 glycoprotein gp120.

As the initial step of the entry of HIV-1 into cells, the interaction of CD4 with gp120 is a central area of concern in HIV-1 biology and intervention studies. CD4 binding induces large conformational changes to gp120, such as the formation of the bridging sheet between the V1/V2 stem and beta20/beta21. Understanding the dynamic process and the mechanism that leads to the formation of the bridging sheet is important.

Oxa-bicyclocalixarenes: a new cage for anions via C-H...anion hydrogen bonds and anion...pi interactions.

Density functional theory calculations indicate that the cage molecule 4 can trap F- in the gas phase (-80.5 kcal/mol) as well as in CH2Cl2 (-14.7 kcal/mol) via strong C-H.

One-pot synthesis of quinoline-based tetracycles by a tandem three-component reaction.

A practical one-pot synthetic strategy for the efficient synthesis of a range of structurally interesting and bioactive quinoline-based tetracycles has been developed. A key step in the synthesis is a tandem three-component reaction of heteroaromatic amine, methyl 2-formylbenzoate and (t)butyl isonitrile, followed by TFA-mediated lactamization via intramolecular aminolysis of an adjacent ester. Results related to a kinase-panel screening for several selected compounds are also discussed in this article.

Theoretical study of the catalytic mechanism and metal-ion dependence of peptide deformylase.

The reaction pathway of deformylation catalyzed by E. coli peptide deformylase (PDF) has been investigated by the density functional theory method of PBE1PBE on a small model and by a two-layer ONIOM method on a realistic protein model. The deformylation proceeds in sequential steps involving nucleophilic addition of metal-coordinated water/hydroxide to the carbonyl carbon of the formyl group, proton transfer, and cleavage of the C-N bond.

A catalytic mechanism revealed by the crystal structures of the imidazolonepropionase from Bacillus subtilis.

Imidazolonepropionase (EC 3.5.2.