Oseltamivir phosphate (OP) is an antiviral drug with potential risks to human health due to overuse, leading to serious consequences such as gastrointestinal disturbances, abnormal neuropsychiatric symptoms, and sudden death. Therefore, gaining an in-depth understanding of its interaction with proteins is crucial. We investigated the interaction between OP and bovine serum albumin (BSA) utilizing multispectral methods (i.e., fluorescence, ultraviolet absorption, circular dichroism) combined with molecular docking techniques. Fluorescence spectroscopy indicated that OP quenched BSA fluorescence by forming the OP-BSA complex. The Stern-Volmer constants (KSV) between OP and BSA were determined to be 3.06 × 103 L/mol, 2.36 × 103 L/mol, and 1.86 × 103 L/mol at 293 K, 298 K, and 303 K, respectively. OP occupies exclusively one binding site on BSA, and the fluorescent probe displacement measurements revealed that this is BSA site I. Thermodynamic data (∆H, ∆S, and ∆G) obtained by fitting the van\'t Hoff equation were - 77.49 kJ/mol, -176.54 J/(mol∙K), and - 24.88 kJ/mol, respectively, suggesting that hydrogen bonding and van der Waals forces mainly participate in OP-BSA complex stabilization. Moreover, the reaction occurs spontaneously at room temperature. Synchronous fluorescence spectra indicated that OP interacts with tryptophan residue of BSA. The results of ultraviolet (UV) and 3D fluorescence spectroscopy indicated that the OP-BSA complex formation altered the microenvironment around amino acid residues. Circular dichroism spectra revealed that the addition of OP decreased the α-helix content of BSA by 7.13%. Docking analysis confirmed that OP binds to BSA site I through hydrogen bonding with amino acids VAL342, SER453, and ASP450. Finally, ADMET studies were conducted to explore the pharmacokinetics of OP as an antiviral drug.

Novel coumarin-piperazine-2(5H)-furanone hybrids 5a-l were efficiently synthesized by introducing a furanone scaffold into coumarin using piperazine as a linker. The cytotoxicity of all hybrids 5a-l were evaluated by MTT assay on human lung cancer A549 cells and normal human lung fibroblast WI-38 cells with cytarabine (CAR) as a positive control. Hybrid 5 l (IC50 = 11.28 μM) was the most toxic to A549 cells, 18-fold more toxic than the reference CAR (IC50 = 202.57 μM). Moreover, hybrid 5 l (IC50 = 411.93 μM) was less toxic to WI-38 cells, with a much higher selectivity (5 l, SI ≈ 37, WI-38/A549) than CAR (SI ≈ 2). Structure-activity relationship analysis showed that both the cytotoxicity against A549 cells and selectivity (WI-38/A549) were greatly improved when the bornyl group was incorporated in the hybrids (5c, 5f, 5i and 5 l). Further, hybrid 5 l was more toxic and selective against four types of human lung cancer cells (A549, Calu-1, PC-9 and H460; IC50 = 5.72-45.46 μM; SI ≈ 9-72) than three other types of human cancer cells (SK-BR-3, 786-O and SK-OV-3, IC50 = 39.07-130.82 μM; SI ≈ 0-2), showing remarkable specificity. In particular, hybrid 5 l (IC50 = 5.72 μM) showed the highest cytotoxicity against H460 cells with the highest selectivity of up to 72 (WI-38/H460). Flow cytometric analysis showed that hybrid 5 l induced apoptosis in H460 cells in a concentration-dependent manner. Molecular docking studies revealed a high binding affinity of hybrid 5 l with CDK2 protein. Hybrid 5 l is expected to be a leading candidate for anti-lung cancer agents.

Streptococcus oralis an opportunistic bacterium has been reported to be involved in various blood borne infections like subacute bacterial endocarditis, septicaemia, bacterial meningitis and in some cases dental caries too. Among various targets the peptide deformylase, of S.oralis appears to be most potent druggable target as it is involved in protein synthesis is opted for the current study. Due to unavailability of PDB structure of peptide deformylase from S. oralis the study initiates with homology modelling of the protein and 6OW2 of S pneumoniae is considered as the template. Thereafter, Molecular docking, Molecular dynamic simulation, ADME analysis, and MMPBSA analysis was carried out to explore the inhibitory potential of phyto-constituents as potential inhibitors for Peptide deformylase from S.oralis. Actinonin was considered as reference drug. Among 2370 phyto compounds the best observations were recorded for A1-Barrigenol (IMPHY010984) with binding affinity of -8.5kcal/mol. Calculated RMSD, RMSF, Binding Free Energy for IMPHY010984 averaged at about 0.10±0.03nm, 0.08±0.05nm, 131±21kJ/mol respectively whereas the RMSD, RMSF, Binding Free Energy recorded for reference drug averaged at about 0.19±0.04nm, 0.11±0.08nm, -94±18kJ/mol respectively. Based on in silico observations IMPHY010984 is proved out as superior candidate over reference drug. The study reflects the potential of IMPHY010984 as prophylactic therapeutics for S.oralis.

UNASSIGNED: Matrine has been reported inhibitory effects on ovarian cancer (OC) cell progression, development, and apoptosis. However, the molecular targets of matrine against OC and the underlying mechanisms of action remain elusive.
UNASSIGNED: This study endeavors to unveil the potential targets of matrine against OC and to explore the intricate relationships between these targets and the pathogenesis of OC.
UNASSIGNED: The effects of matrine on the OC cells (A2780 and AKOV3) viability, apoptosis, migration, and invasion was investigated through CCK-8, flow cytometry, wound healing, and Transwell analyses, respectively. Next, Matrine-related targets, OC-related genes, and ribonucleic acid (RNA) sequence data were harnessed from publicly available databases. Differentially expressed analyses, protein-protein interaction (PPI) network, and Venn diagram were involved to unravel the core targets of matrine against OC. Leveraging the GEPIA database, we further validated the expression levels of these core targets between OC cases and controls. Mendelian randomization (MR) study was implemented to delve into potential causal associations between core targets and OC. The AutoDock software was used for molecular docking, and its results were further validated using RT-qPCR in OC cell lines.
UNASSIGNED: Matrine reduced the cell viability, migration, invasion and increased the cell apoptosis of A2780 and AKOV3 cells (P< 0.01). A PPI network with 578 interactions among 105 candidate targets was developed. Finally, six core targets (TP53, CCND1, STAT3, LI1B, VEGFA, and CCL2) were derived, among which five core targets (TP53, CCND1, LI1B, VEGFA, and CCL2) differential expressed in OC and control samples were further picked for MR analysis. The results revealed that CCND1 and TP53 were risk factors for OC. Molecular docking analysis demonstrated that matrine had good potential to bind to TP53, CCND1, and IL1B. Moreover, matrine reduced the expression of CCND1 and IL1B while elevating P53 expression in OC cell lines.
UNASSIGNED: We identified six matrine-related targets against OC, offering novel insights into the molecular mechanisms underlying the therapeutic effects of matrine against OC. These findings provide valuable guidance for developing more efficient and targeted therapeutic approaches for treating OC.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) are susceptible to coronavirus disease-2019 (COVID-19), but current treatments are limited. Icariside II (IS), a flavonoid compound derived from the plant epimedin, showed anti-cancer,anti-inflammation and immunoregulation effects. The present study aimed to evaluate the possible effect and underlying mechanisms of IS on NSCLC patients with COVID-19 (NSCLC/COVID-19).
METHODS: NSCLC/COVID-19 targets were defined as the common targets of NSCLC (collected from The Cancer Genome Atlas database) and COVID-19 targets (collected from disease database of Genecards, OMIM, and NCBI). The correlations of NSCLC/COVID-19 targets and survival rates in patients with NSCLC were analyzed using the survival R package. Prognostic analyses were performed using univariate and multivariate Cox proportional hazards regression models. Furthermore, the targets in IS treatment of NSCLC/COVID-19 were defined as the overlapping targets of IS (predicted from drug database of TMSCP, HERBs, SwissTarget Prediction) and NSCLC/COVID-19 targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of these treatment targets were performed aiming to understand the biological process, cellular component, molecular function and signaling pathway. The hub targets were analyzed by a protein-protein interaction network and the binding capacity with IS was characterized by molecular docking.
RESULTS: The hub targets for IS in the treatment of NSCLC/COVID-19 includes F2, SELE, MMP1, MMP2, AGTR1 and AGTR2, and the molecular docking results showed that the above target proteins had a good binding degree to IS. Network pharmacology showed that IS might affect the leucocytes migration, inflammation response and active oxygen species metabolic process, as well as regulate the interleukin-17, tumor necrosus factor and hypoxia-inducible factor-1 signaling pathway in NSCLC/COVID-19.
CONCLUSIONS: IS may enhance the therapeutic efficacy of current clinical anti-inflammatory and anti-cancer therapy to benefit patients with NSCLC combined with COVID-19.

The development of targeted phthalazine-1,4-dione acetylcholinesterase (AChE) inhibitors for treating Alzheimer\'s disease involved the synthesis of 32 compounds via a multistage process. Various analytical techniques confirmed the compounds\' identities. Thirteen compounds were found to inhibit AChE by more than 50% without affecting butyrylcholinesterase (BChE). Among these, three compounds, 8m, 8n, and 8p, exhibited extraordinary activity similar to donepezil, a reference AChE inhibitor. During enzyme kinetic studies, compound 8n, displaying the highest AChE inhibitory activity, underwent evaluation at three concentrations (2 × IC50, IC50, and IC50/2). Lineweaver-Burk plots indicated mixed inhibition activity for compound 8n against AChE, suggesting a combination of competitive and noncompetitive characteristics. Additionally, effective derivatives 8m, 8n, and 8p exhibited high blood-brain barrier (BBB) permeability in in vitro parallel artificial membrane permeability assay tests. Molecular docking studies revealed that these compounds bind to the enzyme\'s active site residues in a position similar to donepezil. Molecular dynamic simulations confirmed the stability of the protein-ligand system, and the chemical reactivity characteristics of the compounds were investigated using density functional theory. The compounds\' wide energy gaps suggest stability and therapeutic potential. This research represents a significant step toward finding a potential cure for Alzheimer\'s disease. However, further research and testing are required to determine the compounds\' safety and efficacy. The unique structure of phthalazine derivatives makes them suitable for various biological activities, and these compounds show promise for developing effective drugs for treating Alzheimer\'s disease. Overall, the development of these targeted compounds is a crucial advancement in the search for an effective treatment for Alzheimer\'s disease.

UNASSIGNED: Renshen Yangrong decoction (RSYRD) has been shown therapeutic effects on secondary malaise and fatigue (SMF). However, to date, its bioactive ingredients and potential targets remain unclear.
UNASSIGNED: The purpose of this study is to assess the potential ingredients and targets of RSYRD on SMF through a comprehensive strategy integrating network pharmacology, Mendelian randomization as well as molecular docking verification.
UNASSIGNED: Search for potential active ingredients and corresponding protein targets of RSYRD on TCMSP and BATMAN-TCM for network pharmacology analysis. Mendelian randomization (MR) was performed to find therapeutic targets for SMF. The eQTLGen Consortium (sample sizes: 31,684) provided data on cis-expression quantitative trait loci (cis-eQTL, exposure). The summary data on SMF (outcome) from genome-wide association studies (GWAS) were gathered from the MRC-IEU Consortium (sample sizes: 463,010). We built a target interaction network between the probable active ingredient targets of RSYRD and the therapeutic targets of SMF. We next used drug prediction and molecular docking to confirm the therapeutic value of the therapeutic targets.
UNASSIGNED: In RSYRD, network pharmacology investigations revealed 193 possible active compounds and 234 associated protein targets. The genetically predicted amounts of 176 proteins were related to SMF risk in the MR analysis. Thirty-seven overlapping targets for RSYRD in treating SMF, among which six (NOS3, GAA, IMPA1, P4HTM, RB1, and SLC16A1) were prioritized with the most convincing evidence. Finally, the 14 active ingredients of RSYRD were identified as potential drug molecules. The strong affinity between active components and putative protein targets was established by molecular docking.
UNASSIGNED: This study revealed several active components and possible RSYRD protein targets for the therapy of SMF and provided novel insights into the feasibility of using Mendelian randomization for causal inference between Chinese medical formula and disease.

Through molecular recognition, drugs can interact and complex with macromolecules circulating in the body. The serum albumin transport protein, found in several mammals, has several interaction sites where these molecules can be located. The drug sulfasalazine (SSZ) is known in the literature to complex at drug site 1 (DS1) in human serum (HSA) and bovine serum (BSA) proteins. This complexation can be studied using various spectroscopic techniques. With the techniques used in this work, absorption in the ultraviolet and visible regions (UV-Vis) and electronic circular dichroism (ECD), a significant difference was observed in the results involving HSA and BSA. The application of theoretical methodologies, such as TD-DFT and molecular docking, suggests that the conformation that SSZ assumes in DS1 of the two proteins is different, which exposes it to different amino acid residues and different hydrophobicities. This difference in conformation may be related to the location of DS1 where the drug interacts or to the possibility of SSZ moving in the BSA site, due to its larger size, and moving less freely in HSA.

A very practical method for the synthesis of unsymmetrical carbamide derivatives in good to excellent yield was presented, without the need for any catalyst and at room temperature. Using a facile and robust protocol, fifteen unsymmetrical carbamide derivatives (9-23) bearing different aliphatic amine moieties were designed and synthesized by the reaction of secondary aliphatic amines with isocyanate derivatives in the presence of acetonitrile as an appropriate solvent in good to excellent yields. Trusted instruments like IR, mass spectrometry, NMR spectra, and elemental analyses were employed to validate the purity and chemical structures of the synthesized compounds. All the synthesized compounds were tested as antimicrobial agents against some clinically bacterial pathogens such as Salmonella typhimurium, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Compounds 15, 16, 17, 19 and 22 showed potent antimicrobial activity with promising MIC values compared to the positive controls. Moreover, compounds 15 and 22 provide a potent lipid peroxidation (LPO) of the bacterial cell wall. On the other hand, we investigated the anti-proliferative activity of compounds 9-23 against selected human cancerous cell lines of breast (MCF-7), colon (HCT-116), and lung (A549) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and pro-apoptotic protein markers. The results of MTT assay revealed that compounds 10, 13, 21, 22 and 23 possessed highly cytotoxic effects. Out of these, three synthesized compounds 13, 21 and 22 showed cytotoxicity with IC50 values (13, IC50 = 62.4 ± 0.128 and 22, IC50 = 91.6 ± 0.112 µM, respectively, on MCF-7), (13, IC50 = 43.5 ± 0.15 and 21, IC50 = 38.5 ± 0.17 µM, respectively, on HCT-116). Cell cycle and apoptosis/necrosis assays demonstrated that compounds 13 and 22 induced S and G2/M phase cell cycle arrest in MCF-7 cells, while only compound 13 had this effect on HCT-116 cells. Furthermore, compound 13 exhibited the greatest potency in inducing apoptosis in both cell lines compared to compounds 21 and 22. Docking studies indicated that compounds 10, 13, 21 and 23 could potentially inhibit enzymes and exert promising antimicrobial effects, as evidenced by their lower binding energies and various types of interactions observed at the active sites of key enzymes such as Sterol 14-demethylase of C. albicans, Dihydropteroate synthase of S. aureus, LasR of P. aeruginosa, Glucosamine-6-phosphate synthase of K. pneumenia and Gyrase B of B. subtilis. Moreover, 13, 21, and 22 demonstrated minimal binding energy and favorable affinity towards the active pocket of anticancer receptor proteins, including CDK2, EGFR, Erα, Topoisomerase II and VEGFFR. Physicochemical properties, drug-likeness, and ADME (absorption, distribution, metabolism, excretion, and toxicity) parameters of the selected compounds were also computed.