Identification of novel covalent JAK3 inhibitors through consensus scoring virtual screening: integration of common feature pharmacophore and covalent docking.

Accumulated research strongly indicates that Janus kinase 3 (JAK3) is intricately involved in the initiation and advancement of a diverse range of human diseases, underscoring JAK3 as a promising target for therapeutic intervention. However, JAK3 shows significant homology with other JAK family isoforms, posing substantial challenges in the development of JAK3 inhibitors. To address these limitations, one strategy is to design selective covalent JAK3 inhibitors.

Optimization of virtual screening against phosphoinositide 3-kinase delta: Integration of common feature pharmacophore and multicomplex-based molecular docking.

Extensive research has accumulated which suggests that phosphatidylinositol 3-kinase delta (PI3Kδ) is closely related to the occurrence and development of various human diseases, making PI3Kδ a highly promising drug target. However, PI3Kδ exhibits high homology with other members of the PI3K family, which poses significant challenges to the development of PI3Kδ inhibitors. Therefore, in the present study, a hybrid virtual screening (VS) approach based on a ligand-based pharmacophore model and multicomplex-based molecular docking was developed to find novel PI3Kδ inhibitors.

Molecular modeling strategy for detailing the primary mechanism of action of copanlisib to PI3K: combined ligand-based and target-based approach.

Since dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is associated with the pathogenesis of cancer, inflammation, and autoimmunity, PI3K has emerged as an attractive target for drug development. Although copanlisib is the first pan-PI3K inhibitor to be approved for clinical use, the precise mechanism by which it acts on PI3K has not been fully elucidated. To reveal the binding mechanisms and structure-activity relationship between PI3K and copanlisib, a comprehensive modeling approach that combines 3D-quantitative structure-activity relationship (3D-QSAR), pharmacophore model, and molecular dynamics (MD) simulation was utilized.

Developing new PI3Kγ inhibitors by combining pharmacophore modeling, molecular dynamic simulation, molecular docking, fragment-based drug design, and virtual screening.

Since dysregulation of the phosphatidylinositol 3-kinase gamma (PI3Kγ) signaling pathway is associated with the pathogenesis of cancer, inflammation, and autoimmunity, PI3Kγ has emerged as an attractive target for drug development. IPI-549 is the only selective PI3Kγ inhibitor that has advanced to clinical trials, thus, IPI-549 could serve as a promising template for designing novel PI3Kγ inhibitors. In this present study, a modeling strategy consisting of common feature pharmacophore modeling, receptor-ligand pharmacophore modeling, and molecular dynamics simulation was utilized to identify the key pharmacodynamic characteristic elements of the target compound and the key residue information of the PI3Kγ interaction with the inhibitors.

Modulating the Rise and Decay Dynamics of Upconversion Luminescence through Controlling Excitations.

Different from organic dye/quantum dot possessing one luminescent center, upconversion luminescence (UCL) is actually a statistic of temporal behaviors of countless individual activators. Our experimental results have shown that the rise and decay dynamics of UCL is directly associated with the relative contribution of sensitizer-to-activator energy transfer and energy migration among sensitizers, which can be physically modulated by simply tuning the excitation laser. Therefore, dynamic UCL with record-wide 20-fold lifetime, ≈70-fold red-to-green intensity ratio, and reversibly definable emission color is easily realized by just modulating the excitation laser.

Achieving Multicolor Upconversion Emissions without Changing Compositions.

It is widely recognized that a proper way of adjusting fluorescence color is meaningful for pushing forward upconversion materials to be utilized in anti-counterfeiting, display and solid-state lightning applications. Traditional routes that apply different host materials and/or doping categories to adjust fluorescence color have shown large color region tunability yet have to rely on complex synthesis process accompanied with time and raw material consumption. In this work, in order to get a wide luminous color gamut without depending on reciprocating synthesis, we desinged and provided a high-sensitizer-concentration upconversion crystals, hexagonal NaLuF:Yb/Er (50/2 mol%), whose red-to-green emission intensity ratio can be conveniently tuned from 2.

Theoretical study of myriocin-binding mechanism targeting serine palmitoyltransferase.

Sphingolipids (SLs) are vital for cells as forming membrane and transducing signals. The first step for de novo biosynthesis of SLs is catalyzed by the pyridoxal-5'-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT), which has been proven to be a promising drug target for treating various diseases. However, there are few SPT-specific inhibitors have been identified so far.

Controlling the microbial composition during the fermentation of Ishizuchi-kurocha.

Ishizuchi-kurocha is a popular postfermented tea in Japan. It is performed by domestic and natural fermentation relied on microorganisms derived from tea leaves or the environment of the manufacturing. Ishizuchi-kurocha undergoes aerobic fermentation of fungi first, then second fermented by anaerobic fermentation of lactic acid bacteria during natural fermentation processing.

Targeting phosphatidylinositol 3-kinase gamma (PI3Kγ): Discovery and development of its selective inhibitors.

Phosphatidylinositol 3-kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of advanced solid tumors, leukemia, lymphoma, and inflammatory and autoimmune diseases. However, the high level of structural conservation among the members of the PI3K family and the diverse physiological roles of Class I PI3K isoforms (α, β, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. In this review, we provide an overview of the structural features of PI3Kγ that influence γ-isoform selectivity and discuss the structure-selectivity-activity relationship of existing clinical PI3Kγ inhibitors.

Computer aided optimization of multilinear gradient elution in liquid chromatography.

Analytical expressions for retention time and peak compression factor are deduced by assuming quadratic solvent strength model and multilinear gradient elution. Based on these expressions, a program for the optimization of multilinear gradient profile is written with Visual Basic for Applications in Excel using genetic algorithm. The program is applied to search for a gradient profile for the separation of twelve compounds that are degraded from lignin.

Templated-Construction of Hollow MoS Architectures with Improved Photoresponses.

Despite the outstanding optoelectronic properties of MoS and its analogues, synthesis of such materials with desired features including fewer layers, arbitrary hollow structures, and particularly specifically customized morphologies, via inorganic reactions has always been challenging. Herein, using predesigned lanthanide-doped upconversion luminescent materials (e.g.

Peak compression in linear gradient elution liquid chromatography.

An expression for peak compression factor based on temporal peak widths is proposed which can be measured directly. The relationship between it and peak compression factor based on spatial peak widths is given. The experimental data presented in the Neue's work are reevaluated.

Influence of the pre-elution of solute in initial mobile phase on retention time and peak compression under linear gradient elution.

Under gradient elution the solute will firstly migrate in initial mobile phase due to dwelling time (t) of the system. The pre-elution of solute in initial mobile phase can be accounted for by a dimensionless value of t/(tk), where t and k denote dead time and retention factor in initial mobile phase, respectively. The influence of t/(tk) on retention time (t) and peak compression factor (G) are discussed under linear gradient elution.