China-origin G1 group isolate FPV072 exhibits higher infectivity and pathogenicity than G2 group isolate FPV027.

Introduction: Feline parvovirus (FPV), a single-stranded DNA virus, is accountable for causing feline panleukopenia, a highly contagious and often lethal disease that primarily affects cats. The epidemiology prevalence and pathogenicity of FPV in certain regions of China, however, remains unclear. The aim of this research was to investigate the epidemiology of FPV in different regions of China in 2021 and compare its infectivity and pathogenicity. Methods: In this research, a total of 36 FPV strains were obtained from diverse regions across China. Phylogenetic analysis was performed based on the VP2 and NS1 sequences, and two representative strains, FPV027 and FPV072, which belonged to different branches, were selected for comparative assessment of infectivity and pathogenicity. Results and discussion: The results revealed that all strains were phylogenetically classified into two groups, G1 and G2, with a higher prevalence of G1 strains in China. Both in vitro and in vivo experiments demonstrated that FPV072 (G1 group) exhibited enhanced infectivity and pathogenicity compared to FPV027 (G2 Group). The structural alignment of the VP2 protein between the two viruses revealed mutations in residues 91, 232, and 300 that may contribute to differences in infectivity and pathogenicity. The findings from these observations will contribute significantly to the overall understanding of the molecular epidemiology of FPV in China and facilitate the development of an effective FPV vaccine.

Status of research on natural protein tyrosine phosphatase 1B inhibitors as potential antidiabetic agents: Update.

Protein tyrosine phosphatase 1B (PTP1B) is a crucial therapeutic target for multiple human diseases comprising type 2 diabetes (T2DM) and obesity because it is a seminal part of a negative regulator in both insulin and leptin signaling pathways. PTP1B inhibitors increase insulin receptor sensitivity and have the ability to cure insulin resistance-related diseases. However, the few PTP1B inhibitors that entered the clinic (Ertiprotafib, ISIS-113715, Trodusquemine, and JTT-551) were discontinued due to side effects or low selectivity. Molecules with broad chemical diversity extracted from natural products have been reported to be potent PTP1B inhibitors with few side effects. This article summarizes the recent PTP1B inhibitors extracted from natural products, clarifying the current research progress, and providing new options for designing new and effective PTP1B inhibitors.

Research progress of azido-containing Pt(IV) antitumor compounds.

Cancer is a long-known incurable disease, and the medical use of cisplatin has been a significant discovery. However, the side-effects of cisplatin necessitate the development of new and improved drug. Therefore, in this study, we focused on the photoactivatable Pt(IV) compounds Pt[(X1)(X2)(Y1)(Y2)(N3)2], which have a completely novel mechanism of action. Pt(IV) can efficiently overcome the side-effects of cisplatin and other drugs. Here, we have demonstrated, summarized and discussed the effects and mechanism of these compounds. Compared to the relevant articles in the literature, we have provided a more detailed introduction and a made comprehensive classification of these compounds. We believe that our results can effectively provide a reference for the development of these drugs.

Computer-aided drug design combined network pharmacology to explore anti-SARS-CoV-2 or anti-inflammatory targets and mechanisms of Qingfei Paidu Decoction for COVID-19.

Introduction: Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by SARS-CoV-2. Severe cases of COVID-19 are characterized by an intense inflammatory process that may ultimately lead to organ failure and patient death. Qingfei Paidu Decoction (QFPD), a traditional Chines e medicine (TCM) formula, is widely used in China as anti-SARS-CoV-2 and anti-inflammatory. However, the potential targets and mechanisms for QFPD to exert anti-SARS-CoV-2 or anti-inflammatory effects remain unclear. Methods: In this study, Computer-Aided Drug Design was performed to identify the antiviral or anti-inflammatory components in QFPD and their targets using Discovery Studio 2020 software. We then investigated the mechanisms associated with QFPD for treating COVID-19 with the help of multiple network pharmacology approaches. Results and discussion: By overlapping the targets of QFPD and COVID-19, we discovered 8 common targets (RBP4, IL1RN, TTR, FYN, SFTPD, TP53, SRPK1, and AKT1) of 62 active components in QFPD. These may represent potential targets for QFPD to exert anti-SARS-CoV-2 or anti-inflammatory effects. The result showed that QFPD might have therapeutic effects on COVID-19 by regulating viral infection, immune and inflammation-related pathways. Our work will promote the development of new drugs for COVID-19.

Screening out anti-inflammatory or anti-viral targets in Xuanfei Baidu Tang through a new technique of reverse finding target.

Traditional Chinese herbal compound prescription in Xuanfei Baidu Tang (XBT) has obvious effects in the treatment of COVID-19. However, its effective compounds and targets for the treatment of COVID-19 remain unclear. Computer-Aided Drug Design is used to virtually screen out the anti-inflammatory or anti-viral compounds in XBT, and predict the potential targets by Discovery Studio 2020. Then, we searched for COVID-19 targets using Genecards databases and Protein Data Bank (PDB) databases and compared them to identify targets that were common to both. Finally, the target we screened out is: TP53 (Tumor Protein P53). This article also shows that XBT in the treatment of COVID-19 works in a multi-link and overall synergistic manner. Our results will help to design the new drugs for COVID-19.

Pharmacophore-based drug design of AChE and BChE dual inhibitors as potential anti-Alzheimer's disease agents.

For the Alzheimer's disease (AD) with complex pathogenesis, single target drugs represent one of the most effective therapeutic strategies in clinical. However, the traditional concept of "a disease, a target" is difficult to find very effective drugs, and multi-target drugs have already become new hot spot in drug development for this disease. In our present study, our efforts toward discovering new cholinesterase (ChE) inhibitors aided by computational methods will provide useful information as anti-AD agents in the future. The best 3D-QSAR acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors pharmacophore hypotheses Hypo1 A and Hypo1 B were generated and validated by HypoGen program in Discovery Studio 2016 based on the training set of flavonoids, and then they were used as 3D query for screening the ZINC database. Next, the hit molecules were then subjected to the ADMET and molecular docking study to prioritize the compounds. Finally, 6 compounds showed good estimated activities and promising ADMET properties. The result of best compound ZINC08751495 with AChE estimate activity (0.028), BChE estimate activity (1.55), AChE fit value (9.369), BChE fit value (8.415), AChE -CDOCKER ENERGY (30.22), BChE -CDOCKER ENERGY (33.13) has the potential for further development as a supplement to treat Alzheimer's disease.

Fosfomycin Protects Mice From Staphylococcus aureus Pneumonia Caused by α-Hemolysin in Extracellular Vesicles by Inhibiting MAPK-Regulated NLRP3 Inflammasomes.

α-Hemolysin (Hla) is a significant virulence factor in Staphylococcus aureus (S. aureus)-caused infectious diseases such as pneumonia. Thus, to prevent the production of Hla when treating S. aureus infection, it is necessary to choose an antibiotic with good antibacterial activity and effect. In our study, we observed that Fosfomycin (FOM) at a sub-inhibitory concentration inhibited expression of Hla. Molecular dynamics demonstrated that FOM bound to the binding sites LYS 154 and ASP 108 of Hla, potentially inhibiting Hla. Furthermore, we verified that staphylococcal membrane-derived vesicles (SMVs) contain Hla and that FOM treatment significantly reduced the production of SMVs and Hla. Based on our pharmacological inhibition analysis, ERK and p38 activated NLRP3 inflammasomes. Moreover, FOM inhibited expression of MAPKs and NLRP3 inflammasome-related proteins in S. aureus as well as SMV-infected human macrophages (MΦ) and alveolar epithelial cells. In vivo, SMVs isolated from S. aureus DU1090 (an isogenic Hla deletion mutant) or the strain itself caused weaker inflammation than that of its parent strain 8325-4. FOM also significantly reduced the phosphorylation levels of ERK and P38 and expression of NLRP3 inflammasome-related proteins. In addition, FOM decreased MPO activity, pulmonary vascular permeability and edema formation in the lungs of mice with S. aureus-caused pneumonia. Taken together, these data indicate that FOM exerts protective effects against S. aureus infection in vitro and in vivo by inhibiting Hla in SMVs and blocking ERK/P38-mediated NLRP3 inflammasome activation by Hla.

Molecular dynamics investigation on the Asciminib resistance mechanism of I502L and V468F mutations in BCR-ABL.

Asciminib, a highly selective non-ATP competitive inhibitor of BCR-ABL, has demonstrated to be a promising drug for patients with chronic myeloid leukemia. It is a pity that two resistant mutations (I502L and V468F) have been found during the clinical trial, which is a challenge for the curative effect of Asciminib. In this study, molecular dynamics simulations and molecular mechanics generalized Born surface area (MM-GB/SA) calculations were performed to investigate the molecular mechanism of Asciminib resistance induced by the two mutants. The obtained results indicate that the mutations have adversely influence on the binding of Asciminib to BCR-ABL, as the nonpolar contributions decline in the two mutants. In addition, I502L mutation causes α-helix I' (αI') to shift away from the helical bundle composed of αE, αF, and αH, making the distance between αI' and Asciminib increased. For V468F mutant, the side chain of Phe468 occupies the bottom of the myristoyl pocket (MP), which drives Asciminib to shift toward the outside of MP. Our results provide the molecular insights of Asciminib resistance mechanism in BCR-ABL mutants, which may help the design of novel inhibitors.

Exploring the interactional details between aldose reductase (AKR1B1) and 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid through molecular dynamics simulations.

Aldose reductase (AKR1B1) has been considered as a significant target for designing drugs to counteract the development of diabetic complications. In the present study, molecular dynamics (MD) simulations and molecular mechanics generalized Born surface area (MM-GB/SA) calculations were performed to make sure which tautomer is the preferred one among three tautomeric forms (Mtia1, Mtia2, and Mtia3) of 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (Mtia) for binding to AKR1B1. The overall structural features and the results of calculated binding free energies indicate that Mtia1 and Mtia2 have more superiority than Mtia3 in terms of binding to AKR1B1. Furtherly, the local active site conformational characteristics and non-covalent interaction analysis were identified. The results indicate that the combination of Mtia2 and AKR1B1 is more stable than that of Mtia1. Furthermore, two extra hydrogen bonds between AKR1B1 and Mtia2 are found with respect to Mtia1. In addition, Mtia2 makes slightly stronger electrostatic interaction with the positively charged nicotinamide group of NADP+ than Mtia1. Based on the results above, Mtia2 is the preferred tautomeric form among the three tautomers. Our study can provide an insight into the details of the interaction between AKR1B1 and Mtia at the atomic level, and will be helpful for the further design of AKR1B1 inhibitors.

Exploring the interaction between human focal adhesion kinase and inhibitors: a molecular dynamic simulation and free energy calculations.

Focal adhesion kinase is an important target for the treatment of many kinds of cancers. Inhibitors of FAK are proposed to be the anticancer agents for multiple tumors. The interaction characteristic between FAK and its inhibitors is crucial to develop new inhibitors. In the present article, we used Molecular Dynamic (MD) simulation method to explore the characteristic of interaction between FAK and three inhibitors (PHM16, TAE226, and ligand3). The MD simulation results together with MM-GB/SA calculations show that the combinations are enthalpy-driven process. Cys502 and Asp564 are both essential residues due to the hydrogen bond interactions with inhibitors, which was in good agreement with experimental data. Glu500 can form a non-classical hydrogen bond with each inhibitor. Arg426 can form electrostatic interactions with PHM16 and ligand3, while weaker with TAE226. The electronic static potential was employed, and we found that the ortho-position methoxy of TAE226 has a weaker negative charge than the meta-position one in PHM16 or ligand3. Ile428, Val436, Ala452, Val484, Leu501, Glu505, Glu506, Leu553, Gly563 Leu567, Ser568 are all crucial residues in hydrophobic interactions. The key residues in this work will be available for further inhibitor design of FAK and also give assistance to further research of cancer.

Heparin makes differences: a molecular dynamics simulation study on the human ßII-tryptase monomer.

Human ß-tryptase, an enzyme with trypsin-like activity in mast cells, is an important target for the treatment of inflammatory and allergy related diseases. Heparin has been inferred to play a vital role in the stabilization of the tryptase structure and the maintenance of its active form. Up to now, the structure-function relationship between heparin and the ßII-tryptase monomer has not been studied with atomic resolution due to the lack of a complex structure of tryptase and heparin. To this end, the exact effect of heparin bonding to the ßII-tryptase monomer structure has been investigated using molecular docking and molecular dynamics (MD) simulation. The MD simulation results combined with MM-GB/SA calculations showed that heparin stabilized the ß-tryptase structure mainly through salt bridge interaction. The averaged noncovalent interaction (aNCI) method was employed for the visualization of nonbonding interactions. A crucial loop, which is located in the core region of ßII-tryptase monomer structure, has been found. Arg188 and Asp189 from this loop act as a salt bridge intermediary between 4-mer heparin and 0GX. The observation of a salt bridge between Asp189 and P1 groups of 0GX confirms the supposed interaction between these two groups. These two residues have been proved to be responsible for the direction of the P1 group of 0GX. Our study revealed that how heparin affected the activity of the human ßII-tryptase monomer (hBTM) through salt bridge interactions. The knowledge of heparin binding characteristics and the key residue contributions in this study may enlighten further the inhibitor design of this enzyme and may also improve our understanding of inflammatory and allergy related diseases.