Structural Characterization and Functional Analysis of Mevalonate Kinase from Tribolium castaneum (Red Flour Beetle).

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/ß 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.

IsAb: a computational protocol for antibody design.

The design of therapeutic antibodies has attracted a large amount of attention over the years. Antibodies are widely used to treat many diseases due to their high efficiency and low risk of adverse events. However, the experimental methods of antibody design are time-consuming and expensive. Although computational antibody design techniques have had significant advances in the past years, there are still some challenges that need to be solved, such as the flexibility of antigen structure, the lack of antibody structural data and the absence of standard antibody design protocol. In the present work, we elaborated on an in silico antibody design protocol for users to easily perform computer-aided antibody design. First, the Rosetta web server will be applied to generate the 3D structure of query antibodies if there is no structural information available. Then, two-step docking will be used to identify the binding pose of an antibody-antigen complex when the binding information is unknown. ClusPro is the first method to be used to conduct the global docking, and SnugDock is applied for the local docking. Sequentially, based on the predicted binding poses, in silico alanine scanning will be used to predict the potential hotspots (or key residues). Finally, computational affinity maturation protocol will be used to modify the structure of antibodies to theoretically increase their affinity and stability, which will be further validated by the bioassays in the future. As a proof of concept, we redesigned antibody D44.1 and compared it with previously reported data in order to validate IsAb protocol. To further illustrate our proposed protocol, we used cemiplimab antibody, a PD-1 checkpoint inhibitor, as an example to showcase a step-by-step tutorial.

BamA-targeted antimicrobial peptide design for enhanced efficacy and reduced toxicity.

The emergence of drug-resistant superbugs has necessitated a pressing need for innovative antibiotics. Antimicrobial peptides (AMPs) have demonstrated broad-spectrum antibacterial activity, reduced susceptibility to resistance, and immunomodulatory effects, rendering them promising for combating drug-resistant microorganisms. This study employed computational simulation methods to screen and design AMPs specifically targeting ESKAPE pathogens. Particularly, AMPs were rationally designed to target the BamA and obtain novel antimicrobial peptide sequences. The designed AMPs were assessed for their antibacterial activities, mechanisms, and stability. Molecular docking and dynamics simulations demonstrated the interaction of both designed AMPs, 11pep and D-11pep, with the ß1, ß9, ß15, and ß16 chains of BamA, resulting in misfolding of outer membrane proteins and antibacterial effects. Subsequent antibacterial investigations confirmed the broad-spectrum activity of both 11pep and D-11pep, with D-11pep demonstrating higher potency against resistant Gram-negative bacteria. D-11pep exhibited MICs of 16, 8, and 32 µg/mL against carbapenem-resistant Escherichia coli, carbapenem-resistant Pseudomonas aeruginosa, and multi-drug-resistant Acinetobacter baumannii, respectively, with a concomitant lower resistance induction. Mechanism of action studies confirmed that peptides could disrupt the bacterial outer membrane, aligning with the findings of molecular dynamics simulations. Additionally, D-11pep demonstrated superior stability and reduced toxicity in comparison to 11pep. The findings of this study underscore the efficacy of rational AMP design that targets BamA, along with the utilization of D-amino acid replacements as a strategy for developing AMPs against drug-resistant bacteria.

Computational biology-based study of the molecular mechanism of spermidine amelioration of acute pancreatitis.

Acute pancreatitis (AP) is an acute inflammatory gastrointestinal disease, the mortality and morbility of which has been on the increase in the past years. Spermidine, a natural polyamine, has a wide range of pharmacological effects including anti-inflammation, antioxidation, anti-aging, and anti-tumorigenic. This study aimed to investigate the reliable targets and molecular mechanisms of spermidine in treating AP. By employing computational biology methods including network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we explored the potential targets of spermidine in improving AP with dietary supplementation. The computational biology results revealed that spermidine had high degrees (degree: 18, betweenness: 38.91; degree: 18, betweenness: 206.41) and stable binding free energy (ΔGbind: - 12.81 ± 0.55 kcal/mol, - 15.00 ± 1.00 kcal/mol) with acetylcholinesterase (AchE) and serotonin transporter (5-HTT). Experimental validation demonstrates that spermidine treatment could reduce the necrosis and AchE activity in pancreatic acinar cells. Cellular thermal shift assay (CETSA) results revealed that spermidine could bind to and stabilize the 5-HTT protein in acinar cells. Moreover, spermidine treatment impeded the rise of the expression of 5-HTT in pancreatic tissues of caerulein induced acute pancreatitis mice. In conclusion, serotonin transporter might be a reliable target of spermidine in treating AP. This study provides new idea for the exploration of potential targets of natural compounds.

Three-dimensional quantitative structural-activity relationship and molecular dynamics study of multivariate substituted 4-oxyquinazoline HDAC6 inhibitors.

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.

Discovery of Novel Chinese Medicine Compounds Targeting 3CL Protease by Virtual Screening and Molecular Dynamics Simulation.

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.

Hybrid Metal-Boron Diatomic Site Embedded in C2 N Monolayer Promotes C-C Coupling in CO2 Electroreduction.

Double-atom catalyst (DAC) has gained much interest for its versatile tuning and synergistic effect of dual-atom active sites. Metal (M)-metal (M) diatomic sites, either homo- or heteronuclear, are typically researched. Hybrid metal-non-metal combined sites have rarely been studied and even the viability of such active sites are unknown. Herein, CO2 electroreduction (CO2 RR) is explored on M@X-C2 N (M = Fe, Co, Ni, and Cu; X = S, P, and B) which renders naturally generated M-X diatomic site. Using spin-polarized density functional theory coupled with computational hydrogen electrode model, it is demonstrated that the functionality of hybrid M-B dual-atom center is superior over that of a single- or double-M center in driving CO2 RR especially C-C coupling. Among metal-boron DACs studies, Fe@B-C2 N (µ = 2µB ) exhibits the lowest free energy barrier of 0.17 eV in C-C coupling whereas Ni@B-C2 N (µ = 0µB ) mainly produces CH4 with the lowest barrier of 0.42 eV. Hence, the electronic spin state of M can be particularly important in modulating selectivity and C-C coupling barrier in CO2 RR. Fe@B-C2 N is predicted as the promising catalyst for CO2 RR towards C2+ products owing partially to its enhanced spin state. The findings can enrich the design strategy of electrocatalysts normally running at ambient conditions.

Theoretical Exploring of a Molecular Mechanism for Melanin Inhibitory Activity of Calycosin in Zebrafish.

Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin can lead to a variety of skin disorders. Calycosin is an isoflavone from Astragali Radix, which is a traditional Chinese medicine that exhibits several pharmacological activities including skin whitening. In our study, the inhibitory effect of calycosin on melanin production is confirmed in a zebrafish in vivo model by comparing with hydroquinone, kojic acid, and arbutin, known as tyrosinase inhibitors. Moreover, the inhibitory kinetics of calycosin on tyrosinase and their binding mechanisms are determined using molecular docking techniques, molecular dynamic simulations, and free energy analysis. The results indicate that calycosin has an obvious inhibitory effect on zebrafish pigmentation at the concentration of 7.5 µM, 15 µM, and 30 µM. The IC50 of calycosin is 30.35 µM, which is lower than hydroquinone (37.35 µM), kojic acid (6.51 × 103 µM), and arbutin (3.67 × 104 µM). Furthermore, all the results of molecular docking, molecular dynamics simulations, and free energy analysis suggest that calycosin can directly bind to the active site of tyrosinase with very good binding affinity. The study indicates that the combination of computer molecular modeling and zebrafish in vivo assay would be feasible in confirming the result of the in vitro test and illustrating the target-binding information.

Structural insight into the serotonin (5-HT) receptor family by molecular docking, molecular dynamics simulation and systems pharmacology analysis.

Serotonin (5-HT) receptors are proteins involved in various neurological and biological processes, such as aggression, anxiety, appetite, cognition, learning, memory, mood, sleep, and thermoregulation. They are commonly associated with drug abuse and addiction due to their importance as targets for various pharmaceutical and recreational drugs. However, due to a high sequence similarity/identity among 5-HT receptors and the unavailability of the 3D structure of the different 5-HT receptor, no report was available so far regarding the systematical comparison of the key and selective residues involved in the binding pocket, making it difficult to design subtype-selective serotonergic drugs. In this work, we first built and validated three-dimensional models for all 5-HT receptors based on the existing crystal structures of 5-HT1B, 5-HT2B, and 5-HT2C. Then, we performed molecular docking studies between 5-HT receptors agonists/inhibitors and our 3D models. The results from docking were consistent with the known binding affinities of each model. Sequentially, we compared the binding pose and selective residues among 5-HT receptors. Our results showed that the affinity variation could be potentially attributed to the selective residues located in the binding pockets. Moreover, we performed MD simulations for 12 5-HT receptors complexed with ligands; the results were consistent with our docking results and the reported data. Finally, we carried out off-target prediction and blood-brain barrier (BBB) prediction for Captagon using our established hallucinogen-related chemogenomics knowledgebase and in-house computational tools, with the hope to provide more information regarding the use of Captagon. We showed that 5-HT2C, 5-HT5A, and 5-HT7 were the most promising targets for Captagon before metabolism. Overall, our findings can provide insights into future drug discovery and design of medications with high specificity to the individual 5-HT receptor to decrease the risk of addiction and prevent drug abuse.

Trilobatin, a Novel SGLT1/2 Inhibitor, Selectively Induces the Proliferation of Human Hepatoblastoma Cells.

Studies have indicated that Na+-d-glucose co-transporter (SGLT) inhibitors had anti-proliferative activity by attenuating the uptake of glucose in several tumor cell lines. In this study, the molecular docking showed that, trilobatin, one of the dihydrochalcones from leaves of Lithocarpus polystachyus Rehd., might be a novel inhibitor of SGLT1 and SGLT2, which evidently attenuated the uptake of glucose in vitro and in vivo. To our surprise, we observed that trilobatin did not inhibit, but promoted the proliferation of human hepatoblastoma HepG2 and Huh 7 cells when it was present at high concentrations. At the same time, incubation with high concentrations of trilobatin arrested the cell cycle at S phase in HepG2 cells. We also found that treatment with trilobatin had no significant effect on the expression of hepatitis B x-interacting protein (HBXIP) and hepatocyte nuclear factor (HNF)-4α, the two key regulators of hepatocyte proliferation. Taken together, although trilobatin worked as a novel inhibitor of SGLTs to attenuate the uptake of glucose, it also selectively induced the cell proliferation of HepG2 cells, suggesting that not all the SGLT inhibitors inhibited the proliferation of tumor cells, and further studies are needed to assess the anti-cancer potentials of new glucose-lowering agents.

PD-1-Targeted Discovery of Peptide Inhibitors by Virtual Screening, Molecular Dynamics Simulation, and Surface Plasmon Resonance.

The blockade of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway plays a critical role in cancer immunotherapy by reducing the immune escape. Five monoclonal antibodies that antagonized PD-1/PD-L1 interaction have been approved by the Food and Drug Administration (FDA) and marketed as immunotherapy for cancer treatment. However, some weaknesses of antibodies, such as high cost, low stability, poor amenability for oral administration, and immunogenicity, should not be overlooked. To overcome these disadvantages, small-molecule inhibitors targeting PD-L1 were developed. In the present work, we applied in silico and in vitro approaches to develop short peptides targeting PD-1 as chemical probes for the inhibition of PD-1-PD-L1 interaction. We first predicted the potential binding pocket on PD-1/PD-L1 protein-protein interface (PPI). Sequentially, we carried out virtual screening against our in-house peptide library to identify potential ligands. WANG-003, WANG-004, and WANG-005, three of our in-house peptides, were predicted to bind to PD-1 with promising docking scores. Next, we conducted molecular docking and molecular dynamics (MD) simulation for the further analysis of interactions between our peptides and PD-1. Finally, we evaluated the affinity between peptides and PD-1 by surface plasmon resonance (SPR) binding technology. The present study provides a new perspective for the development of PD-1 inhibitors that disrupt PD-1-PD-L1 interactions. These promising peptides have the potential to be utilized as a novel chemical probe for further studies, as well as providing a foundation for further designs of potent small-molecule inhibitors targeting PD-1.

Combined pharmacophore modeling, 3D-QSAR, homology modeling and docking studies on CYP11B1 inhibitors.

The mitochondrial cytochrome P450 enzymes inhibitor steroid 11ß-hydroxylase (CYP11B1) can decrease the production of cortisol. Therefore, these inhibitors have an effect in the treatment of Cushing's syndrome. A pharmacophore model generated by Genetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets (GALAHAD) was used to align the compounds and perform comparative molecular field analysis (CoMFA) with Q2 = 0.658, R2 = 0.959. The pharmacophore model contained six hydrophobic regions and one acceptor atom, and electropositive and bulky substituents would be tolerated at the A and B sites, respectively. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study based on the alignment with the atom root mean square (RMS) was applied using comparative molecular field analysis (CoMFA) with Q2 = 0.666, R2 = 0.978, and comparative molecular similarity indices analysis (CoMSIA) with Q2 = 0.721, R2 = 0.972. These results proved that all the models have good predictability of the bioactivities of inhibitors. Furthermore, the QSAR models indicated that a hydrogen bond acceptor substituent would be disfavored at the A and B groups, while hydrophobic groups would be favored at the B site. The three-dimensional (3D) model of the CYP11B1 was generated based on the crystal structure of the CYP11B2 (PDB code 4DVQ). In order to probe the ligand-binding modes, Surflex-dock was employed to dock CYP11B1 inhibitory compounds into the active site of the receptor. The docking result showed that the imidazolidine ring of CYP11B1 inhibitors form H bonds with the amino group of residue Arg155 and Arg519, which suggested that an electronegative substituent at these positions could enhance the activities of compounds. All the models generated by GALAHAD QSAR and Docking methods provide guidance about how to design novel and potential drugs for Cushing's syndrome treatment.

A convenient four-component one-pot synthesis of 2-amino-1,3,4-thiadiazoles in water.

A novel four-component one-pot approach for the synthesis of 2-amino-1,3,4-thiadiazoles from primary amines, carbon disulfide, hydrazine, and acyl chlorides has been developed. A series of 5-substituted-2-amino-1,3,4-thiadiazoles were synthesized in medium-to-good yields utilizing this newly developed method.

Development and Evaluation of a Water-Free In Situ Depot Gel Formulation for Long-Acting and Stable Delivery of Peptide Drug ACTY116.

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.

Cardiovascular adverse events associated with antibody-drug conjugates (ADCs): a pharmacovigilance study based on the FAERS database.

Objective: As a novel drug formulation, antibody drug conjugates (ADCs) are widely used in various types of cancer. However, clinically, there is a lack of attention to the CVD produced by them, as well as a lack of research on the real-world situation. Using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, to ensure its clinical safety application, we analyzed post-marketing data on antitumor ADCs to identify risk factors and drugs associated with the risk of cardiovascular events. Research design and methods: We used OpenVigil 2.1 to conduct a database query for adverse events (AEs) reported to the FAERS database between the time the drug was launched and the second quarter of 2023. Cardiovascular adverse events (AEs) were grouped into fourteen narrow categories using the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs), and the reporting odds ratio (ROR) and the proportional reporting ratio (PRR) for reporting the association between different drugs and cardiovascular disease (CVD) risk were calculated. Results: In the FAERS database, 1863 AEs associated with CVD we studied were identified in patients receiving ADC therapy. Most reports came from people aged ≥65, but a significant number of cases were found to be unknown. The number of patients with antibody-drug conjugates (ADCs)-related CVD cases aged <18 years, 18-64 years, and≥ 65 years was 52 (2.79%), 586 (31.45%), and 613 (32.90%), respectively. The proportion of female patients (834, 44.77%) was higher than that of male patients (752, 40.37%). Death (770 reports), disability (9 reports), Hospitalization initial or prolonged (407 reports), and life-threatening reactions (187 reports). Of the 770 deaths reported, 103 (31.7%) were associated with brentuximab vedotin, 10 (24.4%) with sacituzumab govitecan, 22 (19.3%) with enfortumab vedotin, and 35 (34.7%) with trastuzumab emtansine.49 (41.2%) cases were associated with polatuzumab vedotin, 62 (29%) with trastuzumab deruxtecan, 423 (54.3%) with gemtuzumab ozogamicin, and 66 (38.8%) with inotuzumab ozogamicin. In a disproportionate number of SMQS, cardiac failure (n = 277) and embolic and thrombotic events, venous (n = 446) were the most frequently reported CVD-related AEs in ADCs. Conclusion: By mining the FAERS database, we provided relevant information on the association between ADC use and cardiovascular-associated AEs. ADCs were associated with increased cardiovascular toxicity, deserving distinct monitoring and appropriate management. Further research is needed to confirm these findings and assess causality.

Circular RNAs in programmed cell death: Regulation mechanisms and potential clinical applications in cancer: A review.

Circular RNAs (circRNAs) are a novel class of non-coding RNAs with covalently closed structures formed by reverse splicing of precursor mRNAs. The widespread expression of circRNAs across species has been revealed by high-throughput sequencing and bioinformatics approaches, indicating their unique properties and diverse functions including acting as microRNA sponges and interacting with RNA-binding proteins. Programmed cell death (PCD), encompassing various forms such as apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis, is an essential process for maintaining normal development and homeostasis in the human body by eliminating damaged, infected, and aging cells. Many studies have demonstrated that circRNAs play crucial roles in tumourigenesis and development by regulating PCD in tumor cells, showing that circRNAs have the potential to be biomarkers and therapeutic targets in cancer. This review aims to comprehensively summarize the intricate associations between circRNAs and diverse PCD pathways in tumor cells, which play crucial roles in cancer development. Additionally, this review provides a detailed overview of the underlying mechanisms by which circRNAs modulate various forms of PCD for the first time. The ultimate objective is to offer valuable insights into the potential clinical significance of developing novel strategies based on circRNAs and PCD for cancer diagnosis, prognosis, and treatment.

Eliminating Voids and Residual PbI2 beneath a Perovskite Film via Buried Interface Modification for Efficient Solar Cells.

The commercialization process of perovskite solar cells (PSCs) is markedly restricted by the power conversion efficiency (PCE) and long-term stability. During fabrication and operation, the bottom interface of the organic-inorganic hybrid perovskite layer frequently exhibits voids and residual PbI2, while these defects inevitably act as recombination centers and degradation sites, affecting the efficiency and stability of the devices. Therefore, the degradation and nonradiative recombination originating from the buried interface should be thoroughly resolved. Here, we report a multifunctional passivator by introducing malonic dihydrazide as an interfacial chemical bridge between the electron transport layer and the perovskite (PVK) layer. MADH with hydrazine groups improves the surface affinity of SnO2 and provides nucleation sites for the growth of PVK, leading to the reduced residual PbI2 and the voids resulting from the inhomogeneous solvent volatilization at the bottom interface. Meanwhile, the hydrazine group and carbonyl group synergistically coordinate with Pb2+ to improve the crystal growth environment, reducing the number of Pb-related defects. Eventually, the PCE of the PSCs is significantly enhanced benefiting from the reduced interfacial defects and the increased carrier transport. Moreover, the reductive nature of hydrazide further inhibits I2 generation during long-term operation, and the device retains 90% of the initial PCE under a 1 sun continuous illumination exposure of 700 h.

Virtual screening and biological activity evaluation of novel efflux pump inhibitors targeting AdeB.

The AdeABC efflux pump is an important mechanism causing multidrug resistance in Acinetobacter baumannii, and its main component AdeB can recognize carbapenems, aminoglycosides, and other multi-class antibiotics and efflux them intracellularly, which is an ideal target for the development of anti-multidrug resistant bacteria drugs. Here, we combined multiple computer-aided drug design methods to target AdeB to identify promising novel structural inhibitors. Virtual screening was performed by molecular docking and molecular dynamics simulation (MD) and 12 potential compounds were identified from the databases. Meanwhile, their biological activities were validated by in vitro activity assays, and ChemDiv L676-2179 (γ-IFN), ChemDiv L676-1461, and Chembridge 53717615 were confirmed to suppress efflux effects and restore antibiotic susceptibility of resistant bacteria, which are expected to be developed as adjuvant drugs for the treatment of multi-drug resistant Acinetobacter baumannii clinical infections.

Pharmacological mechanism of quercetin in the treatment of colorectal cancer by network pharmacology and molecular simulation.

Colorectal cancer is a serious threat to people's life due to its high incidence and high mortality. Quercetin can effectively treat colorectal carcinoma (CRC), but its exact mechanism of action is still unclear. Then quercetin-related target genes were obtained from Swiss Target Prediction database and Similarity Ensemble Approach (SEA) database, and CRC-related target genes were obtained from GeneCards database, respectively. Common target genes were obtained by FunRich software. String software was used to construct a protein-protein interaction (PPI) network. R package was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Molecular docking, molecular dynamics (MD) simulation and post-dynamics simulation were used to explore the binding stability of quercetin to key targets. In total, 103 and 141 target information of quercetin were obtained from the Swiss Target Prediction database and SEA database, respectively. 1,649 CRC-related genes were obtained from GeneCards database. FunRich software was used to draw venny map and obtain 36 intersection targets of quercetin and CRC. String software was used to construct the PPI network. The core genes were AKT1, EGFR, MMP9, KDR, MET and PTK2. There were 532 items related to biological processes, 14 items related to cellular components, and 43 items related to molecular functions among the key target GO enrichment items. KEGG enrichment pathways of key targets involved cancer pathways, PI3K-Akt signal pathway, etc. The results of molecular docking, MD simulation and post-dynamics simulation showed they had a good affinity and formed a stable effect. So quercetin may play an important role in the treatment of CRC by acting on AKT1, EGFR, MMP9, KDR, MET and PTK2 to affect the development of CRC.Communicated by Ramaswamy H. Sarma.

Non-classical digestive lipase BmTGL selected by gene amplification reduces the effects of mulberry inhibitor during silkworm domestication.

Efficient utilization of dietary lipids is crucial for Bombyx mori, also known as domesticated silkworms. However, the effects of domestication on the genes encoding lipases remain unknown. In this study, we investigated the expression difference of one triacylglycerol lipase (BmTGL) between B.mori and wild (ancestor) silkworm strains (Bombyx mandarina). An immunofluorescence localization analysis showed that BmTGL was present in all parts of the gut and was released into the intestinal lumen. BmTGL expression was significantly enhanced in different domesticated silkworm strains compared to that in the B. mandarina strains. The BmTGL copy numbers in the genomes of the domesticated silkworm strains were 2-to-3 folds that of the B. mandarina strains and accounted for the enhanced expression of BmTGL in the domesticated silkworm strains. The Ser144Asn substitution in the Ser-Asp-His catalytic triads of BmTGL resulted in relatively lower lipase activity and reduced sensitivity to the lipase inhibitor morachalcone A. Moreover, BmTGL overexpression significantly increased the weights of the B. mori silkworms compared to those of the non-transgenic controls. Thus, the selection of BmTGL by gene amplification may be a trade-off between maintaining high enzymatic activity and reducing the effects of mulberry inhibitors during silkworm domestication.