Vol 20, No 3 (2024)

Background:Studies have indicated that Sinomenii Caulis (SC) has several physiological activities, such as anti-inflammatory, anti-cancer, immunosuppression, and so on. SC is currently widely used in the treatment of rheumatoid arthritis, skin disease, and other diseases. However, the mechanism of SC in the treatment of ulcerative colitis (UC) remains unclear.

Aims:To predict the active components of SC and determine the mechanism of SC on UC.

Methods:Active components and targets of SC were screened and obtained by TCMSP, PharmMapper, and CTD databases. The target genes of UC were searched from GEO (GSE9452), and DisGeNET databases. Based on the String database, Cytoscape 3.7.2 software, and David 6.7 database, we analyzed the relationship between SC active components and UC potential targets or pathways. Finally, identification of SC targets in anti-UC by molecular docking. GROMACS software was used to perform molecular dynamics simulations of protein and compound complexes and to perform free energy calculations.

Results:Six main active components, 61 potential anti-UC gene targets, and the top 5 targets with degree value are IL6, TNF, IL1β, CASP3, and SRC. According to GO enrichment analysis, the vascular endothelial growth factor receptor and vascular endothelial growth factor stimulus may be relevant biological processes implicated in the treatment of UC by SC. The KEGG pathway analysis result was mainly associated with the IL-17, AGE-RAGE, and TNF signaling pathways. Based on molecular docking results, beta-sitosterol, 16-epi-Isositsirikine, Sinomenine, and Stepholidine are strongly bound to the main targets. Molecular dynamics simulation results showed that IL1B/beta-sitosterol and TNF/16-epi-Isositsirikine binding was more stable.

Conclusion:SC can play a therapeutic role in UC through multiple components, targets, and pathways. The specific mechanism of action needs to be further explored.

Background:Discovery of novel antimicrobial agents is in need to deal with antibiotic resistance. Elucidating the mechanism of action for established drugs contributes to this endeavor. DNA gyrase is a therapeutic target used in the design and development of new antibacterial agents. Selective antibacterial gyrase inhibitors are available; however, resistance development against them is a big challenge. Hence, novel gyrase inhibitors with novel mechanisms are required.

Objective:The aim of this study is to elucidate mode of action for existing DNA gyrase inhibitors and to pave the way towards discovery of novel inhibitors.

Methods:In this study, the mechanism of action for selected DNA gyrase inhibitors available was carried out through molecular docking and molecular dynamics (MD) simulation. In addition, pharmacophore analysis, density functional theory (DFT) calculations, and computational pharmacokinetics analysis of the gyrase inhibitors were performed.

Results:This study demonstrated that all the DNA gyrase inhibitors investigated, except compound 14, exhibit their activity by inhibiting gyrase B at a binding pocket. The interaction of the inhibitors at Lys103 was found to be essential for the binding. The molecular docking and MD simulation results revealed that compound 14 could act by inhibiting gyrase A. A pharmacophore model that consisted of the features that would help the inhibition effect was generated. The DFT analysis demonstrated 14 had relatively high chemical stability. Computational pharmacokinetics analysis revealed that most of the explored inhibitors were estimated to have good drug-like properties. Furthermore, most of the inhibitors were found to be non-mutagenic.

Conclusion:In this study, mode of action elucidation through molecular docking and MD simulation, pharmacophore model generation, pharmacokinetic property prediction, and DFT study for selected DNA gyrase inhibitors were carried out. The outcomes of this study are anticipated to contribute to the design of novel gyrase inhibitors.

Background:Cancer is one of the most dangerous illnesses to the human body due to its severity and progressive nature. Kaposi's Sarcoma (KS) tumor can appear as painless purple spots on the legs, foot, or face. This cancer develops in the lining of lymph arteries and blood vessels. Along with the enlargement of lymph nodes, the vaginal region and the mouth portion are the additional target areas of KS. DNA-binding proteins known as Sox proteins are found in all mammals and belong to the HMG box superfamily. They controlled a wide range of developmental procedures, such as the formation of the germ layer, the growth of organs, and the selection of the cell type. Human developmental abnormalities and congenital illnesses are frequently caused by the deletion or mutation of the Sox protein.

Aim:The purpose of this study is to determine the promising Kaposi's sarcoma inhibitors through computational studies.

Objective:In this present study computational approaches were used to evaluate the anti- carcinogenic efficacy against Kaposi's sarcoma.

Methods:Ligand-based pharmacophore screening was performed utilising four different chemical libraries (Asinex, Chembridge, Specs, and NCI Natural products (NSC)) depending on the top hypothesis. The top hits were examined using molecular docking, absorption, distribution, metabolism and excretion. Highest occupied molecular orbital and lowest unoccupied molecular orbital were analysed to determine the lead compounds' biological and pharmacological efficacy. The results of the study indicated that the leading candidates were possible SOX protein inhibitors.

Conclusion:The results revealed that the top hits responded to all of the pharmacological druglikening criteria and had the best interaction residues, fitness scores, and docking scores. The resulting leads might be potential Kaposi's Sarcoma alternative treatments.

Background:SARS-CoV-2 is a life-threatening virus in the world. Scientific evidence indicates that this pathogen will emerge again in the future. Although the current vaccines have a pivotal role in the control of this pathogen, the emergence of new variants has a negative impact on their effectiveness.

Objective:Therefore, it is urgent to consider the protective and safe vaccine against all subcoronavirus species and variants based on the conserved region of the virus. Multi-epitope peptide vaccine (MEV), comprised of immune-dominant epitopes, is designed by immunoinformatic tools and it is a promising strategy against infectious diseases.

Methods:Spike glycoprotein and nucleocapsid proteins from all coronavirus species and variants were aligned and the conserved region was selected. Antigenicity, toxicity, and allergenicity of epitopes were checked by a proper server. To robust the immunity of the multi-epitope vaccine, cholera toxin b (CTB) and three HTL epitopes of tetanus toxin fragment C (TTFrC) were linked at the N-terminal and C-terminal of the construct, respectively. Selected epitopes with MHC molecules and the designed vaccines with Toll-like receptors (TLR-2 and TLR-4) were docked and analyzed. The immunological and physicochemical properties of the designed vaccine were evaluated. The immune responses to the designed vaccine were simulated. Furthermore, molecular dynamic simulations were performed to study the stability and interaction of the MEV-TLRs complexes during simulation time by NAMD (Nanoscale molecular dynamic) software. Finally, the codon of the designed vaccine was optimized according to Saccharomyces boulardii.

Results:The conserved regions of spike glycoprotein and nucleocapsid protein were gathered. Then, safe and antigenic epitopes were selected. The population coverage of the designed vaccine was 74.83%. The instability index indicated that the designed multi-epitope was stable (38.61). The binding affinity of the designed vaccine to TLR2 and TLR4 was -11.4 and -11.1, respectively. The designed vaccine could induce humoral and cellular immunity.

Conclusion:In silico analysis showed that the designed vaccine is a protective multi-epitope vaccine against SARS-CoV-2 variants.

Background:Drug re-purposing is one of the cost-effective methods to establish novel therapeutics against many diseases. Established natural products are collected from databases and used to potentially screen them against HPV E6 protein, a critical viral protein.

Objective:This study aims to design potential small molecule inhibitors against HPV E6 protein using structure-based approaches. Ten natural anti-cancerous compounds (Apigenin, Baicalein, Baicalin, Ponicidin, Oridonin, Lovastatin, Triterpenoid, Narirutin, Rosmarinic Acid, and Xanthone) were selected by review of the literature.

Methods:These compounds were screened using Lipinski Rule of Five. Out of ten compounds, seven were found to satisfy Rule of five. Docking of these seven compounds was carried out using AutoDock software and corresponding Molecular Dynamics Simulations were performed by GROMACS.

Results:Among the seven compounds docked with the E6 target protein, six compounds showed lesser binding energy than the reference compound, Luteolin. The three-dimensional structures of E6 protein and the corresponding ligand complexes were visualised and analysed using PyMOL whereas the two-dimensional images of protein-ligand interactions were obtained by LigPlot+ software to study the specific interactions. ADME analysis using SwissADME software revealed that all the compounds except Rosmarinic acid have good gastrointestinal absorption and solubility characteristics while Xanthone and Lovastatin showed blood brain barrier penetration properties. Considering the binding energy and ADME analysis, Apigenin and Ponicidin are found to be most suitable for de novo designing of potential inhibitors against the HPV16 E6 protein.

Conclusion:Further, synthesis and characterization of these potential HPV16 E6 inhibitors will be carried out and their functional evaluation using cell culture-based assays will be undertaken.