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In situ depot gel is a type of polymeric long-acting injectable (pLAI) drug delivery system; compared to microsphere technology, its preparation process is simpler and more conducive to industrialization. To ensure the chemical stability of peptide ACTY116, we avoided the use of harsh conditions such as high temperatures, high shear mixing, or homogenization; maintaining a water-free and oxygen-free environment was also critical to prevent hydrolysis and oxidation. Molecular dynamics (MDs) simulations were employed to assess the stability mechanism between ACTY116 and the pLAI system. The initial structure of ACTY116 with an alpha helix conformation was constructed using SYBYL-X, and the copolymer PLGA was generated by AMBER 16; results showed that PLGA-based in situ depot gel improved conformational stability of ACTY116 through hydrogen bonds formed between peptide ACTY116 and the components of the pLAI formulation, while PLGA (Poly(DL-lactide-co-glycolide)) also created steric hindrance and shielding effects to prevent conformational changes. As a result, the chemical and conformational stability and in vivo long-acting characteristics of ACTY116 ensure its enhanced efficacy. In summary, we successfully achieved our objective of developing a highly stable peptide-loaded long-acting injectable (LAI) in situ depot gel formulation that is stable for at least 3 months under harsh conditions (40 °C, above body temperature), elucidating the underlying stabilisation mechanism, and the high stability of the ACTY116 pLAI formulation creates favourable conditions for its in vivo pharmacological activity lasting for weeks or even months. [ABSTRACT FROM AUTHOR]

Mevalonate kinase (MevK) is an important enzyme in the mevalonate pathway that catalyzes the phosphorylation of mevalonate into phosphomevalonate and is involved in juvenile hormone biosynthesis. Herein, we present a structure model of MevK from the red flour beetle Tribolium castaneum (TcMevK), which adopts a compact α/β conformation that can be divided into two parts: an N-terminal domain and a C-terminal domain. A narrow, deep cavity accommodating the substrate and cofactor was observed at the junction between the two domains of TcMevK. Computational simulation combined with site-directed mutagenesis and biochemical analyses allowed us to define the binding mode of TcMevK to cofactors and substrates. Moreover, TcMevK showed optimal enzyme activity at pH 8.0 and an optimal temperature of 40 °C for mevalonate as the substrate. The expression profiles and RNA interference of TcMevK indicated its critical role in controlling juvenile hormone biosynthesis, as well as its participation in the production of other terpenoids in T. castaneum. These findings improve our understanding of the structural and biochemical features of insect Mevk and provide a structural basis for the design of MevK inhibitors. [ABSTRACT FROM AUTHOR]

[Objective] A lightweight SE-PPM algorithm (SAPMDSNet) was proposed to solve the problems of slow speed, misclassification and difficulty in feature extraction in traditional positive and subgroup classification of natural state tobacco leaves. [Method] Based on the lightweight ShuffleNetV2 net-work, the training speed of the network model was accelerated by reducing the network convolution depth and evolving the activation function. Then, the channel attention SE module was introduced to enhance the haracteristic differences between channels, improve the representation ability of the network model and a-void the group misclassification caused by the regionalization. Finally, the pyramid pooling module PPM was embedded to integrate the exposure characters and global information by aggregating context information, and the in-house tobacco leaf data set was used and compared with other models. [Result] The SAPMDSNet network model achieved relatively high classification results with accuracy of 91.09% and FLOPs of 151.70 M. Compared with the original ShuffleNetV2 model and the lightweight GhostNet model, the FLOPs were slightly increased by 2.65% and 2.84%, and the accuracy was increased by 2.72% and 21.13 %, respectively. MobileNetV2, DenseNet and SqueezeNet achieved recognition accuracies of 87.02%, 89.53% and 87.60%, which were close to the proposed model, but their FLOPs were significantly higher. [Conclusion] The constructed SAPMDSNet network model improved the classification accuracy of positive and sub-group tobacco leaves in natural state with better overall performance, which provides a new method for primary screening of tobacco leaves. [ABSTRACT FROM AUTHOR]

Regulating the structural and interfacial properties of transition metal phosphides (TMPs) by coupling carbon-based materials with large surface areas to enhance hydrogen evolution reaction (HER) performance presents significant progress for water splitting technology. Herein, we constructed a composite substrate of a three-dimensional porous graphene oxide matrix (3D-GO) embedded in nickel foam (NF) to grow a Co2P electrocatalyst. Well-defined gladiolus-like Co2P nanowire arrays tightly anchored on the substrate show enhanced electrochemical characteristics for the hydrogen evolution reaction (HER) based on the promoting roles of 3D porous reduced GO (3D-rGO) derived from 3D-GO, which promotes the dispersion of active components, improves the rate of electron transfer, and facilitates the transport of water molecules. As a result, the obtained Co2P@3D-rGO/NF electrode exhibits superior HER activity in 1.0 M KOH media, achieving overpotentials of 36.5 and 264.7 mV at current densities of 10 and 100 mA cm−2, respectively. The electrode also has a low Tafel slope of 55.5 mV dec−1, a large electrochemical surface area, and small charge-transfer resistance, further revealing its mechanism of high intrinsic activity. Moreover, the electrode exhibits excellent HER stability and durability without surface morphology and chemical state changes. [ABSTRACT FROM AUTHOR]

3D-QSAR models were established by collecting 46 multivariate-substituted 4-oxyquinazoline HDAC6 inhibitors. The relationship of molecular structure and inhibitory activity was studied by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). The results showed the models established by CoMFA (q2 = 0.590, r2 = 0.965) and CoMSIA (q2 = 0.594, r2 = 0.931) had good prediction ability. At the same time, 3D-QSAR models met the internal verification, external verification and AD test. Ten new compounds were designed based on CoMFA and CoMSIA contour maps and their pharmacokinetic/toxic properties (ADME/T) were evaluated. It was found that most compounds have well safety profile and pharmacokinetic property. Then, we explored the interaction between HDAC6 and compounds by molecular docking. The results showed that the binding mode of the new compounds with HDAC6 was the same as the template compound 46, and the hydrogen bond and hydrophobic bond played a vital role in the binding process. Molecular dynamics simulation results showed that residues Ser531, His574 and Tyr745 played key roles in the binding process. All newly designed compounds had lower energy gap and binding energy than compound 46 according to DFT analysis and free energy analysis. This study provided a theoretical reference for designing compounds of higher activity and a new idea for the development of novel HDAC6 inhibitors. [ABSTRACT FROM AUTHOR]

The rational passivation of the defects at the buried interface plays a significant role in reducing energy loss and improving the photovoltaic performance of perovskite solar cells (PSCs). Herein, we have applied a metal–organic framework (MOF)-based host–guest system consisting of zeolitic imidazolate framework-8 (ZIF-8) nanosheets confined with methylammonium chloride (MACl) to modify the SnO2/perovskite interface. The MACl@ZIF-8 not only effectively reduces the oxygen vacancies on SnO2, but also binds with the uncoordinated Pb2+ and halogen ions at the bottom of the perovskite layer. Moreover, the loaded MACl guest plays the role of both crystalline seeds involved in the formation of ZIF-8@perovskite heterojunctions and organic cation vacancy passivators. Thus, the simultaneous passivation of the buried interface and bulk phase of the perovskite is realized, and the photovoltaic performance of devices is enhanced considerably with an optimal efficiency of 22.10%. The introduction of MACl@ZIF-8 also allows the device to achieve excellent moisture stability due to better crystallinity and fewer phase defects. In particular, the UV shielding characteristic of the imidazole ligands in ZIF-8 results in a significant increase in the UV resistance capability. [ABSTRACT FROM AUTHOR]

Myocarditis is classified as an inflammatory disease of the heart muscle and is a leading cause of sudden death. The Keap1-Nrf2-ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1-Nrf2 protein–protein interaction (PPI) is considered as a potential drug target against myocarditis to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes. To gain insights into the relationship between the activity and structure of the compounds and design superior active novel inhibitors, 3D-QSAR, molecular docking and molecular dynamics (MD) simulation were combined to investigate the interaction between Keap1–Nrf2 PPI inhibitors and Keap1. The comparative molecular field analysis (CoMFA) model (q2 = 0.907, n = 7, R2 = 0.997) and the comparative molecular similarity index analysis (CoMSIA) model (q2 = 0.900, n = 7, and R2 = 0.993) showed that the 3D-QSAR models built were credible and predictable. Based on these models, 10 new compounds were discovered and their bioactivity was validated using molecular docking and MD simulation. Furthermore, the plausible ADME/T characteristics of new compounds were evaluated and the key residues (Arg415, Tyr334, Ser602, Ser363, Arg380, etc.) in the active site were also identified by free energy calculation. The binding energy results show that the structurally optimized compounds (N1: −65.409 kcal mol−1, N3: −54.619 kcal mol−1, N4: −62.627 kcal mol−1, N5: −60.903 kcal mol−1, and N8: −66.272 kcal mol−1) have lower binding free energy values than compound 43 (ΔGbind: −49.991 kcal mol−1), indicating that they have a better affinity for the target. These findings provide necessary theoretical guidance for the discovery and design of highly active drugs against myocarditis. [ABSTRACT FROM AUTHOR]

The transmission and infectivity of COVID-19 have caused a pandemic that has lasted for several years. This is due to the constantly changing variants and subvariants that have evolved rapidly from SARS-CoV-2. To discover drugs with therapeutic potential for COVID-19, we focused on the 3CL protease (3CLpro) of SARS-CoV-2, which has been proven to be an important target for COVID-19 infection. Computational prediction techniques are quick and accurate enough to facilitate the discovery of drugs against the 3CLpro of SARS-CoV-2. In this paper, we used both ligand-based virtual screening and structure-based virtual screening to screen the traditional Chinese medicine small molecules that have the potential to target the 3CLpro of SARS-CoV-2. MD simulations were used to confirm these results for future in vitro testing. MCCS was then used to calculate the normalized free energy of each ligand and the residue energy contribution. As a result, we found ZINC15676170, ZINC09033700, and ZINC12530139 to be the most promising antiviral therapies against the 3CLpro of SARS-CoV-2. [ABSTRACT FROM AUTHOR]