Virtual screening based on pharmacophore model for developing novel HPPD inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for herbicide design. A multilayered virtual screening workflow was constructed by combining two pharmacophore models based on ligand and crystal complexes, molecular docking, molecular dynamics (MD), and biological activity determination to identify novel small-molecule inhibitors of HPPD. About 110, 000 compounds of Bailingwei and traditional Chinese medicine databases were screened. Of these, 333 were analyzed through docking experiments. Five compounds were selected by analyzing the binding pattern of inhibitors with amino acid residues in the active pocket. All five compounds could produce stable coordination with cobalt ion, and form favorable π-π interactions. MD simulation demonstrated that Phe381 and Phe424 made large contributions to the strength of binding. The enzyme activity experiment verified that compound-139 displayed excellent potency against AtHPPD (IC50 = 0.742 µM), however, compound-5222 had inhibitory effect on human HPPD (IC50 = 6 nM). Compound-139 exhibited herbicidal activity to some extent on different gramineous weeds. This work provided a strong insight into the design and development of novel HPPD inhibitor using in silico techniques.

A Multifunctional and Fast-Response Lysosome-Targetable Fluorescent Probe for Monitoring pH and Isoxaflutole.

A new chemosensor, namely N-(2-morpholinoethyl)acetamide-4-morpholine-1,8-naphthimide (MMN), was designed and synthesized through an amidation reaction. MMN was fabricated as a multifunctional fluorescent probe for monitoring pH and isoxaflutole. MMN exhibited excellent stability in MeCN/H2O (v/v, 9/1), with an obvious "off-on" fluorescence response toward pH changes due to intramolecular charge transfer (ICT), where the linear response ranges of MMN in the weakly acidic system were from 4.2 to 5.0 and from 5.0 to 6.0 with apparent pKa = 4.62 ± 0.02 and 5.43 ± 0.02. Based on morpholine as the lysosome targetable unit, MMN could selectively locate lysosomes in live cells. MMN also successfully detected the presence of H+ in test papers. Finally, MMN could specifically recognize isoxaflutole at a detection limit of 0.88 µM. A possible sensing mechanism was identified based on density function theory calculations. These results indicate that MMN could be a superior potential chemosensor for detecting pH and isoxaflutole selectively and sensitively and could be used in real sample detection.

Computer-Aided and AILDE Approaches to Design Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a pivotal enzyme in tocopherol and plastoquinone synthesis and a potential target for novel herbicides. Thirty-five pyridine derivatives were selected to establish a Topomer comparative molecular field analysis (Topomer CoMFA) model to obtain correlation information between HPPD inhibitory activity and the molecular structure. A credible and predictive Topomer CoMFA model was established by "split in two R-groups" cutting methods and fragment combinations (q2 = 0.703, r2 = 0.957, ONC = 6). The established model was used to screen out more active compounds and was optimized through the auto in silico ligand directing evolution (AILDE) platform to obtain potential HPPD inhibitors. Twenty-two new compounds with theoretically good HPPD inhibition were obtained by combining the high-activity contribution substituents in the existing molecules with the R-group search via Topomer search. Molecular docking results revealed that most of the 22 fresh compounds could form stable π-π interactions. The absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction and drug-like properties made 9 compounds potential HPPD inhibitors. Molecular dynamics simulation indicated that Compounds Y12 and Y14 showed good root mean square deviation (RMSD) and root mean square fluctuation (RMSF) values and stability. According to the AILDE online verification, 5 new compounds with potential HPPD inhibition were discovered as HPPD inhibitor candidates. This study provides beneficial insights for subsequent HPPD inhibitor design.

NPA-Cu2+ Complex as a Fluorescent Sensing Platform for the Selective and Sensitive Detection of Glyphosate.

Glyphosate is a highly effective, low-toxicity, broad-spectrum herbicide, which is extensively used in global agriculture to control weeds and vegetation. However, glyphosate has become a potential threat to human and ecosystem because of its excessive usage and its bio-concentration in soil and water. Herein, a novel turn-on fluorescent probe, N-n-butyl-4-(3-pyridin)ylmethylidenehydrazine-1,8-naphthalimide (NPA), is proposed. It efficiently detected Cu2+ within the limit of detection (LOD) of 0.21 µM and displayed a dramatic turn-off fluorescence response in CH3CN. NPA-Cu2+ complex was employed to selectively and sensitively monitor glyphosate concentrations in real samples accompanied by a fluorescence turn-on mode. A good linear relationship between NPA and Cu2+ of glyphosate was found in the range of 10-100 µM with an LOD of 1.87 µM. Glyphosate exhibited a stronger chelation with Cu2+ than NPA and the system released free NPA through competitive coordination. The proposed method demonstrates great potential in quantitatively detecting glyphosate in tap water, local water from Songhua River, soil, rice, millet, maize, soybean, mung bean, and milk with mild conditions, and is a simple procedure with obvious consequences and no need for large instruments or pretreatment.

The functional roles of chemokines and chemokine receptors in colorectal cancer progression.

Colorectal cancer is a common malignancy with significant rates of morbidity and mortality. A number of factors, including the tumor microenvironment, chemokines, the inflammatory response, have an impact on the development of colorectal cancer. A critical component of the tumor microenvironment is chemokines. Various cell subsets are attracted to the tumor microenvironment through interactions with chemokine receptors. These cells have varying effects on the development of the tumor and the effectiveness of treatment. Additionally, chemokines can participate in inflammatory processes and have effects that are either pro- or anti-tumor. Chemokines can be exploited as targets for medication resistance and treatment in colorectal cancer. In this review, we discuss the expression of chemokines and chemokine receptors, and their relationship with immune cells in the tumor microenvironment. At the same time, we also collect and discuss the significance of chemokines and chemokine receptors in colorectal cancer progression, and their potential as molecular targets for CRC treatment.

Sensitive fluorescence assay for the detection of glyphosate with NACCu2+ complex.

Glyphosate is widely used as an herbicide in weed control. However, the excessive use and residue of glyphosate adversely affect the environment. Thus, a rapid and highly sensitive system must be developed for glyphosate detection. Herein, a novel turn-on fluorescent probe was designed and synthesized for glyphosate, that is N-butyl-1,8-naphthalimide-4-hydrazino-6-isopropyl-chromone (NAC). The fluorescence of NAC was quenched by the addition of Cu2+ to form NACCu2+ complex in dimethyl sulfoxide/2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (DMSO/HEPES, 9/1, v/v, pH = 7.0). Upon the addition of glyphosate, the fluorescence of NACCu2+ was recovered through chelation between Cu2+ and glyphosate. The NACCu2+ complex exhibited the desired linearity of glyphosate concentration under optimum conditions in the range of 0-40 µM with a low detection limit of 36 nM. Based on competitive coordination, NACCu2+ exhibited good sensitivity and selectivity for glyphosate. Moreover, NAC was successfully utilized to detect glyphosate in tap water, local water from Songhua River, soil, maize, and soybean with convenient operations, indicating a promising application in pesticide residue detection.

Strong and stiff aramid nanofiber/carbon nanotube nanocomposites.

Small but strong carbon nanotubes (CNTs) are fillers of choice for composite reinforcement owing to their extraordinary modulus and strength. However, the mechanical properties of the nanocomposites are still much below those for mechanical parameters of individual nanotubes. The gap between the expectation and experimental results arises not only from imperfect dispersion and poor load transfer but also from the unavailability of strong polymers that can be effectively utilized within the composites of nanotubes. Aramid nanofibers (ANFs) with analogous morphological features to nanotubes represent a potential choice to complement nanotubes given their intrinsic high mechanical performance and the dispersible nature, which enables solvent-based processing methods. In this work, we showed that composite films made from ANFs and multiwalled CNTs (MWCNTs) by vacuum-assisted flocculation and vacuum-assisted layer-by-layer assembly exhibited high ultimate strength of up to 383 MPa and Young's modulus (stiffness) of up to 35 GPa, which represent the highest values among all the reported random CNT nanocomposites. Detailed studies using different imaging and spectroscopic characterizations suggested that the multiple interfacial interactions between nanotubes and ANFs including hydrogen bonding and π-π stacking are likely the key parameters responsible for the observed mechanical improvement. Importantly, our studies further revealed the attractive thermomechanical characteristics of these nanocomposites with high thermal stability (up to 520 °C) and ultralow coefficients of thermal expansion (2-6 ppm·K(-1)). Our results indicated that ANFs are promising nanoscale building blocks for functional ultrastrong and stiff materials potentially extendable to nanocomposites based on other nanoscale fillers.

Hydrogen Bonding Stabilized Self-Assembly of Inorganic Nanoparticles: Mechanism and Collective Properties.

Developing a simple and efficient method to organize nanoscale building blocks into ordered superstructures, understanding the mechanism for self-assembly and revealing the essential collective properties are crucial steps toward the practical use of nanostructures in nanotechnology-based applications. In this study, we showed that the high-yield formation of ZnO nanoparticle chains with micrometer length can be readily achieved by the variation of solvents from methanol to water. Spectroscopic studies confirmed the solvent effect on the surface properties of ZnO nanoparticles, which were found to be critical for the formation of anisotropic assemblies. Quantum mechanical calculations and all atom molecular dynamic simulations indicated the contribution of hydrogen bonding for stabilizing the structure in water. Dissipative particle dynamics further revealed the importance of solvent-nanoparticle interactions for promoting one-dimensional self-assembly. The branching of chains was found upon aging, resulting in the size increase of the ensembles and network formation. Steady-state and time-resolved luminescent spectroscopes, which probed the variation of defect-related emission, revealed stronger Forster resonance energy transfer (FRET) between nanoparticles when the chain networks were formed. The high efficiency of FRET quenching can be ascribed to the presence of multiple energy transfer channels, as well as the short internanoparticle distances and the dipole alignment.