Virtual screening and molecular dynamics simulation of natural compounds as potential inhibitors of serine/threonine kinase 16 for anticancer drug discovery.

Serine/threonine kinase 16 (STK 16) is involved in many facets of cellular regulation; activation of STK 16 plays a crucial role in the migration of cancer cells. Therefore, it is a novel target for the discovery of anticancer agents. Herein, virtual screening and dynamics simulation were used to screen a large library of natural compounds against STK 16 using Schrodinger suit 2021-2 and GROMACS 2021.6. The results predicted five molecules with high binding affinity against the target, with NPC132329 (Arcyriaflavin C) and NPC160898 having higher binding affinity and molecular mechanics generalized born surface area (MM/GBSA), suggesting that it is better than the standard inhibitor. The molecular dymanics (MD) simulation studies showed that the STK 16-NPC132329 complex has the lowest root mean square deviation, and STK 16-NPC160898 was the most stable compared with the standard drug and selective STK 16 inhibitor. The minimal fluctuation was observed in the STK 16-NPC132329 and STK 16-NPC160898 complexes based on the root mean square fluctuation trajectory with NPC132329 and NPC160898 forming 2 and 3 hydrogen bonds respectively with the amino acid residue of the target's binding site. Overall, NPC132329 and NPC160898 are better STK 16 inhibitors than the standard drug and selective inhibitor, which can be further studied to discover novel anticancer drugs.

Unlocking the biological potential of transition metal complexes with Thiosemicarbazone ligands: Insights from computational studies.

In the previous study, the synthesis and characterization of 4-(3-fluorophenyl)-3-thiosemicarbazide and benzaldehyde derivatives based thiosemicarbazone ligands and their Co(II), Ni(II), Cu(II), Zn(II) complexes were carried out to evaluate their malarial and oxidant and inflammatory inhibition abilities, demonstrating that these compounds have robust efficacy for these ailments. In the present research, to find out a combating agent against breast cancer, tuberculosis, bacterial and fungal ailments, the compounds were tested through MTT, microplate alamar blue and serial dilution protocols. ADMET and DFT investigation were analyzed against highly bioactive compounds (2, 7-10) to give a new insight about compound's reactivity, stability and drug likeness properties. Furthermore, activity results shows that the ligand (2) and its complexes demonstrate greater efficacy compared to ligand (1) and its complexes. The Cu(II) (9) and Zn(II) (10) complexes were observed as highly efficient for breast cancer (MCF-7 cell line), TB (H37Rv strain), bacterial and fungal ailments in comparison of standard drugs with 0.029 ± 0.001 µM IC50 value for (9) in anticancer activity and 0.0034 ± 0.0017 µmol/mL MIC value for (10) in anti-tuberculosis activity. In the molecular docking investigation, the various kind of binding interactions and lowest binding affinity of (9) (against 4RJ3 (-10.0 kcal/mol), 2VCJ (-7.9 kcal/mol)) and (10) (-7.8 and -8.3 kcal/mol for 5V3Y and 3PTY protein) support their bioactivity. This research highlights the pharmaceutical importance of transition metal complexes having thiosemicarbazones, presenting a significant approach for the discovery of potent anti-infectious agent.

In vitro and in silico investigation of effects of antimicrobial peptides from Solanaceae plants against rice sheath blight pathogen Rhizoctinia solani.

Rhizoctonia solani, the causative agent of sheath blight disease in rice, poses a significant threat to agricultural productivity. Traditional management approaches involving chemical fungicides have been effective but come with detrimental consequences for the ecosystem. This study aimed to investigate sustainable alternatives in the form of antifungal peptides derived from Solanaceous plant species as potential agents against R. solani. Peptide extracts were obtained using an optimized antimicrobial peptide (AMP) extraction method and desalted using the solid-phase extraction technique. The antifungal potential of peptide-rich extracts from Solanum tuberosum and Capsicum annum was assessed through in vitro tests employing the agar well diffusion method. Furthermore, peptide-protein docking analysis was performed on HPEPDOCK and HDOCK server; and molecular dynamics simulations (MDS) of 100 ns period were performed using the Gromacs 2020.4. The results demonstrated significant inhibition zones for both extracts at concentrations of 100 mg/mL. Additionally, the extracts of Solanum tuberosum and Capsicum annum had minimum inhibitory concentrations of 50 mg/mL and 25 mg/mL, respectively with minimum fungicidal concentrations of 25 mg/mL. Insights into the potential mechanisms of key peptides inhibiting R. solani targets were gleaned from in-silico studies. Notably, certain AMPs exhibited favorable free energy of binding against pathogenicity-related targets, including histone demethylase, sortin nexin, and squalene synthase, in protein-peptide docking simulations. Extended molecular dynamics simulations lasting 100 ns and MM-PBSA calculations were performed on select protein-peptide complexes. AMP10 displayed the most favorable binding free energy against all target proteins, with AMP3, AMP12b, AMP6, and AMP15 also exhibiting promising results against specific targets of R. solani. These findings underscore the potential of peptide extracts from S. tuberosum and C. annum as effective antifungal agents against rice sheath blight caused by R. solani.

In-silico formulation of a next-generation polyvalent vaccine against multiple strains of monkeypox virus and other related poxviruses.

Mpox (formerly known as monkeypox) virus and some related poxviruses including smallpox virus pose a significant threat to public health, and effective prevention and treatment strategies are needed. This study utilized a reverse vaccinology approach to retrieve conserved epitopes for monkeypox virus and construct a vaccine that could provide cross-protection against related viruses with similar antigenic properties. The selected virulent proteins of monkeypox virus, MPXVgp165, and Virion core protein P4a, were subjected to epitope mapping for vaccine construction. Two vaccines were constructed using selected T cell epitopes and B cell epitopes with PADRE and human beta-defensins adjuvants conjugated in the vaccine sequence. Both constructs were found to be highly antigenic, non-allergenic, nontoxic, and soluble, suggesting their potential to generate an adequate immune response and be safe for humans. Vaccine construct 1 was selected for molecular dynamic simulation studies. The simulation studies revealed that the TLR8-vaccine complex was more stable than the TLR3-vaccine complex. The lower RMSD and RMSF values of the TLR8 bound vaccine compared to the TLR3 bound vaccine suggested better stability and consistency of hydrogen bonds. The Rg values of the vaccine chain bound to TLR8 indicated overall stability, whereas the vaccine chain bound to TLR3 showed deviations throughout the simulation. These results suggest that the constructed vaccine could be a potential preventive measure against monkeypox and related viruses however, further experimental validation is required to confirm these findings.

Development of multi epitope subunit vaccines against emerging carp viruses Cyprinid herpesvirus 1 and 3 using immunoinformatics approach.

Cyprinid herpesvirus is a causative agent of a destructive disease in common and koi carp (Cyprinus carpio), which leads to substantial global financial losses in aquaculture industries. Among the strains of C. herpesvirus, C. herpesvirus 1 (CyHV-1) and C. herpesvirus 3 (CyHV-3) are known as highly pathogenic to carp fishes in Europe, Asia, and Africa. To date, no effective vaccine has been developed to combat these viruses. This study aimed to develop unique multi-epitope subunit vaccines targeting the CyHV-1 and CyHV-3 using a reverse vaccinology approach. The study began with a comprehensive literature review to identify the most critical proteins, which were then subjected to in silico analyses to predict highly antigenic epitopes. These analyses involved assessing antigenicity, transmembrane topology screening, allergenecity, toxicity, and molecular docking approaches. We constructed two multi-epitope-based vaccines incorporating a suitable adjuvant and appropriate linkers. It revealed that both the vaccines are non-toxic and immunogenic. The tertiary structures of the vaccine proteins were generated, refined, and validated to ensure their suitability. The binding affinity between the vaccine constructs and TLR3 and TLR5 receptors were assessed by molecular docking studies. Molecular dynamics simulations indicated that vaccine construct V1 exhibited greater stability with both TLR3 and TLR5 based on RMSD analysis. Hydrogen bond analysis revealed a stronger binding affinity between the vaccine constructs and TLR5 compared to TLR3. Furthermore, MM-PBSA analysis suggested that both vaccine constructs exhibited a better affinity for TLR5. Considering all aspects, the results suggest that in silico development of CyHV vaccines incorporating multiple epitopes holds promise for management of diseases caused by CyHV-1 and CyHV-3. However, further in vivo trials are highly recommended to validate the efficacies of these vaccines.

Antifungal plant flavonoids identified in silico with potential to control rice blast disease caused by Magnaporthe oryzae.

Rice blast disease, caused by the fungus Magnaporthe oryzae, poses a severe threat to rice production, particularly in Asia where rice is a staple food. Concerns over fungicide resistance and environmental impact have sparked interest in exploring natural fungicides as potential alternatives. This study aimed to identify highly potent natural fungicides against M. oryzae to combat rice blast disease, using advanced molecular dynamics techniques. Four key proteins (CATALASE PEROXIDASES 2, HYBRID PKS-NRPS SYNTHETASE TAS1, MANGANESE LIPOXYGENASE, and PRE-MRNA-SPLICING FACTOR CEF1) involved in M. oryzae's infection process were identified. A list of 30 plant metabolites with documented antifungal properties was compiled for evaluation as potential fungicides. Molecular docking studies revealed that 2-Coumaroylquinic acid, Myricetin, Rosmarinic Acid, and Quercetin exhibited superior binding affinities compared to reference fungicides (Azoxystrobin and Tricyclazole). High throughput molecular dynamics simulations were performed, analyzing parameters like RMSD, RMSF, Rg, SASA, hydrogen bonds, contact analysis, Gibbs free energy, and cluster analysis. The results revealed stable interactions between the selected metabolites and the target proteins, involving important hydrogen bonds and contacts. The SwissADME server analysis indicated that the metabolites possess fungicide properties, making them effective and safe fungicides with low toxicity to the environment and living beings. Additionally, bioactivity assays confirmed their biological activity as nuclear receptor ligands and enzyme inhibitors. Overall, this study offers valuable insights into potential natural fungicides for combating rice blast disease, with 2-Coumaroylquinic acid, Myricetin, Rosmarinic Acid, and Quercetin standing out as promising and environmentally friendly alternatives to conventional fungicides. These findings have significant implications for developing crop protection strategies and enhancing global food security, particularly in rice-dependent regions.

Identification of ß-cycloidal-derived mono-carbonyl curcumin analogs as potential interleukin-6 inhibitor to treat wound healing through QSAR, molecular docking, MD simulation, MM-GBSA calculation.

Interleukin-6 (IL-6) is a cytokine that involved in the different phases of wound healing. It is responsible for promoting inflammation, regulating tissue repair scar formation, stimulating the production of extracellular matrix components and recruiting immune cells to the wound site. Therefore, suppressing IL-6 is beneficial for wound healing. However, no small molecules are currently available in the market against the IL-6. As a result, this research gap motivates us to find a potential inhibitor. This study aimed to investigate the wound healing potential of novel ß-cycloidal-derived mono-carbonyl curcumin analogs reported in the literature through screening a series of computational studies. The calculated pIC50 value of 18 compounds (below 10) showed that all compounds may have potential therapeutic efficacy. Molecular docking studies revealed that compound C12 (-45.6044 kcal/mol) bound most strongly in the active site of IL-6 compared to the FDA-approved drug clindamycin (-42.3223). The Molecular Dynamic (MD) simulation displayed that lead compound C12 had the highest stability in the active site of IL-6 compared to the reference drug clindamycin. Furthermore, MMGBSA results indicated that C12 (-20.28 kcal/mol) had the highest binding energy compared to clindamycin (-8.36 kcal/mol). The ADMET analysis predicted that C12 are favourable for drug candidates. This study recommended compound C12 as a lead IL-6 inhibitor for future testing and development as therapeutics for wound healing.Communicated by Ramaswamy H. Sarma.

Exploring antibiofilm potential of some new imidazole analogs against C. albicans: synthesis, antifungal activity, molecular docking and molecular dynamics studies.

A series of 1, 2, 4, 5-tetrasubstituted imidazole derivatives were synthesized and their antibiofilm potential against Candida albicans was evaluated in vitro. Two of the synthesized derivatives 5e (IC50 = 25 µg/mL) and 5m (IC50 = 6 µg/mL),displayed better antifungal and antibiofilm potential than the standard drug Fluconazole (IC50 = 40 µg/mL) against C. albicans. Based on the in vitro results, we escalated the real time polymerase chain reaction (RT-PCR) analysis to gain knowledge of the enzymes expressed in the generation and maintenance of biofilms and the mechanism of biofilm inhibition by the synthesized analogues. We then investigated the possible interactions of the synthesized compounds in inhibiting agglutinin-like proteins, namely Als3, Als4 and Als6 were prominently down-regulated using in-silico molecular docking analysis against the previously available crystal structure of Als3 and constructed structure of Als4 and Als6 using the SWISS-MODEL server. The stability and energy of the agglutinin-like proteins-ligand complexes were evaluated using molecular dynamics simulations (MDS). According to the 100 ns MDS, all the compounds remained stable, formed a maximum of 3, and on average 2 hydrogen bonds, and Gibb's free energy landscape analysis suggested greater affinity of the compounds 5e and 5m toward Als4 protein.Communicated by Ramaswamy H. Sarma.

Neomangiferin, a Naturally Occurring Mangiferin Congener, Inhibits Sodium-Glucose Co-transporter-2: An In silico Approach.

Type 2 diabetes is a major health concern contributing to most of diabetic cases worldwide. Mangiferin and its congeners are known for their diverse pharmacological properties. This study sought to investigate the inhibitory property of naturally occurring mangiferin congeners on sodium-glucose co-transporter 2 protein (SGLT-2) using comprehensive computational methods. The naturally occurring mangiferin congeners were subjected to molecular docking, molecular dynamics (MDs) simulation (100 ns), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy, density functional theory calculations (B3LYP 6-31G basis set), and ADMET approaches to identify potential SGLT-2 inhibitor. The molecular docking studies revealed neomangiferin (-9.0 kcal/mol) as the hit molecule compared with dapagliflozin (-8.3 kcal/mol). Root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) plots from the MD simulations established that neomangiferin stabilizes SGLT-2 better than the dapagliflozin, a standard drug. The MM-PBSA binding free energy calculations showed that neomangiferin (-26.05 kcal/mol) elicited better binding affinity than dapagliflozin (-17.42 kcal/mol). The electronic studies showed that neomangiferin (3.48 eV) elicited high electrophilicity index compared with mangiferin (3.31 eV) and dapagliflozin (2.11 eV). Also, the ADMET properties showed that the hit molecule is safe when administered to diabetic subjects. The current in silico studies suggest that neomangiferin could emerge as a promising lead molecule as a SGLT-2 inhibitor.

Correction: An immunoinformatics and extended molecular dynamics approach for designing a polyvalent vaccine against multiple strains of Human T-lymphotropic virus (HTLV).

[This corrects the article DOI: 10.1371/journal.pone.0287416.].

Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study.

Background and Objectives: PON1 is a multi-functional antioxidant protein that hydrolyzes a variety of endogenous and exogenous substrates in the human system. Growing evidence suggests that the Leu55Met and Gln192Arg substitutions alter PON1 activity and are linked with a variety of oxidative-stress-related diseases. Materials and Methods: We implemented structural modeling and molecular dynamics (MD) simulation along with essential dynamics of PON1 and molecular docking with their endogenous (n = 4) and exogenous (n = 6) substrates to gain insights into conformational changes and binding affinity in order to characterize the specific functional ramifications of PON1 variants. Results: The Leu55Met variation had a higher root mean square deviation (0.249 nm) than the wild type (0.216 nm) and Gln192Arg (0.202 nm), implying increased protein flexibility. Furthermore, the essential dynamics analysis confirms the structural change in PON1 with Leu55Met vs. Gln192Arg and wild type. Additionally, PON1 with Leu55Met causes local conformational alterations at the substrate binding site, leading to changes in binding affinity with their substrates. Conclusions: Our findings highlight the structural consequences of the variants, which would increase understanding of the role of PON1 in the pathogenesis of oxidative-stress-related diseases, as well as the management of endogenous and exogenous chemicals in the treatment of diseases.

An immunoinformatics and extended molecular dynamics approach for designing a polyvalent vaccine against multiple strains of Human T-lymphotropic virus (HTLV).

Human T-lymphotropic virus (HTLV), a group of retroviruses belonging to the oncovirus family, has long been associated with various inflammatory and immunosuppressive disorders. At present, there is no approved vaccine capable of effectively combating all the highly pathogenic strains of HTLV that makes this group of viruses a potential threat to human health. To combat the devastating impact of any potential future outbreak caused by this virus group, our study employed a reverse vaccinology approach to design a novel polyvalent vaccine targeting the highly virulent subtypes of HTLV. Moreover, we comprehensively analyzed the molecular interactions between the designed vaccine and corresponding Toll-like receptors (TLRs), providing valuable insights for future research on preventing and managing HTLV-related diseases and any possible outbreaks. The vaccine was designed by focusing on the envelope glycoprotein gp62, a crucial protein involved in the infectious process and immune mechanisms of HTLV inside the human body. Epitope mapping identified T cell and B cell epitopes with low binding energies, ensuring their immunogenicity and safety. Linkers and adjuvants were incorporated to enhance the vaccine's stability, antigenicity, and immunogenicity. Initially, two vaccine constructs were formulated, and among them, vaccine construct-2 exhibited superior solubility and structural stability. Molecular docking analyses also revealed strong binding affinity between the vaccine construct-2 and both targeted TLR2 and TLR4. Molecular dynamics simulations demonstrated enhanced stability, compactness, and consistent hydrogen bonding within TLR-vaccine complexes, suggesting a strong binding affinity. The stability of the complexes was further corroborated by contact, free energy, structure, and MM-PBSA analyses. Consequently, our research proposes a vaccine targeting multiple HTLV subtypes, offering valuable insights into the molecular interactions between the vaccine and TLRs. These findings should contribute to developing effective preventive and treatment approaches against HTLV-related diseases and preventing possible outbreaks. However, future research should focus on in-depth validation through experimental studies to confirm the interactions identified in silico and to evaluate the vaccine's efficacy in relevant animal models and, eventually, in clinical trials.

Subtractive proteomics analysis to uncover the potent drug targets for distinctive drug design of Candidaauris.

Candida auris is a serious health concern of the current world that possesses a serious global health threat and is emerging at a high rate. Available antifungal drugs are failing to combat this pathogen as they are growing resistant to those drugs and some strains have already shown resistance to all three available antifungal drugs in the market. Hence, finding alternative therapies is essential for saving lives from this enemy. To make the development of new treatments easier, we conducted some in silico study of this pathogen to discover possible targets for drug design and also recommended some possible metabolites to test in vivo circumstances. The complete proteome of the representative strain was retrieved, and the duplicate, non-essential, human homologous, non-metabolic, and druggable proteins were then eliminated. As a result, out of a total of 5441 C. auris proteins, we were able to isolate three proteins (XP 028890156.1, XP 028891672.1, and XP 028891858.1) that are crucial for the pathogen's survival as well as host-non-homolog, metabolic, and unrelated proteins to the human microbiome. Their subcellular locations and interactions with a large number of proteins (10 proteins) further point to them being good candidates for therapeutic targets. Following in silico docking of 29 putative antifungals of plant origin against the three proteins we chose, Caledonixanthone E, Viniferin, Glaucine, and Jatrorrhizine were discovered to be the most effective means of inhibiting those proteins since they displayed higher binding affinities (ranging from -28.97 kcal/mol to -51.99 kcal/mol) than the control fluconazole (which ranged between -28.84 kcal/mol and -41.15 kcal/mol). According to the results of MD simulations and MM-PBSA calculations, Viniferin and Caledonixanthone E are the most effective ligands for the proteins XP 028890156.1, XP 028891672.1, and XP 028891858.1. Furthermore, they were predicted to be safe and also showed proper ADME properties.

Synergistic Inhibitory Effect of Quercetin and Cyanidin-3O-Sophoroside on ABCB1.

The human ABCB1 (P-glycoprotein, Pgp) protein is an active exporter expressed in the plasma membrane of cells forming biological barriers. In accordance with its broad substrate spectrum and tissue expression pattern, it affects the pharmacokinetics of numerous chemotherapeutic drugs and it is involved in unwanted drug-drug interactions leading to side effects or toxicities. When expressed in tumor tissues, it contributes to the development of chemotherapy resistance in malignancies. Therefore, the understanding of the molecular details of the ligand-ABCB1 interactions is of crucial importance. In a previous study, we found that quercetin (QUR) hampers both the transport and ATPase activity of ABCB1, while cyandin-3O-sophroside (C3S) stimulates the ATPase activity and causes only a weak inhibition of substrate transport. In the current study, when QUR and C3S were applied together, both a stronger ATPase inhibition and a robust decrease in substrate transport were observed, supporting their synergistic ABCB1 inhibitory effect. Similar to cyclosporine A, a potent ABCB1 inhibitor, co-treatment with QUR and C3S shifted the conformational equilibrium to the "inward-facing" conformer of ABCB1, as it was detected by the conformation-selective UIC2 mAb. To gain deeper insight into the molecular details of ligand-ABCB1 interactions, molecular docking experiments and MD simulations were also carried out. Our in silico studies support that QUR and C3S can bind simultaneously to ABCB1. The most favourable ligand-ABCB1 interaction is obtained when C3S binds to the central substrate binding site and QUR occupies the "access tunnel". Our results also highlight that the strong ABCB1 inhibitory effect of the combined treatment with QUR and C3S may be exploited in chemotherapy protocols for the treatment of multidrug-resistant tumors or for improving drug delivery through pharmacological barriers.

A computational approach to design a polyvalent vaccine against human respiratory syncytial virus.

Human Respiratory Syncytial Virus (RSV) is one of the leading causes of lower respiratory tract infections (LRTI), responsible for infecting people from all age groups-a majority of which comprises infants and children. Primarily, severe RSV infections are accountable for multitudes of deaths worldwide, predominantly of children, every year. Despite several efforts to develop a vaccine against RSV as a potential countermeasure, there has been no approved or licensed vaccine available yet, to control the RSV infection effectively. Therefore, through the utilization of immunoinformatics tools, a computational approach was taken in this study, to design a multi-epitope polyvalent vaccine against two major antigenic subtypes of RSV, RSV-A and RSV-B. Potential predictions of the T-cell and B-cell epitopes were followed by extensive tests of antigenicity, allergenicity, toxicity, conservancy, homology to human proteome, transmembrane topology, and cytokine-inducing ability. The peptide vaccine was modeled, refined, and validated. Molecular docking analysis with specific Toll-like receptors (TLRs) revealed excellent interactions with suitable global binding energies. Additionally, molecular dynamics (MD) simulation ensured the stability of the docking interactions between the vaccine and TLRs. Mechanistic approaches to imitate and predict the potential immune response generated by the administration of vaccines were determined through immune simulations. Subsequent mass production of the vaccine peptide was evaluated; however, there remains a necessity for further in vitro and in vivo experiments to validate its efficacy against RSV infections.

Molecular Docking Identifies 1,8-Cineole (Eucalyptol) as A Novel PPARγ Agonist That Alleviates Colon Inflammation.

Inflammatory bowel disease, comprising Crohn's disease (CD) and ulcerative colitis (UC), is often debilitating. The disease etiology is multifactorial, involving genetic susceptibility, microbial dysregulation, abnormal immune activation, and environmental factors. Currently, available drug therapies are associated with adverse effects when used long-term. Therefore, the search for new drug candidates to treat IBD is imperative. The peroxisome proliferator-activated receptor-γ (PPARγ) is highly expressed in the colon. PPARγ plays a vital role in regulating colonic inflammation. 1,8-cineole, also known as eucalyptol, is a monoterpene oxide present in various aromatic plants which possess potent anti-inflammatory activity. Molecular docking and dynamics studies revealed that 1,8-cineole binds to PPARγ and if it were an agonist, that would explain the anti-inflammatory effects of 1,8-cineole. Therefore, we investigated the role of 1,8-cineole in colonic inflammation, using both in vivo and in vitro experimental approaches. Dextran sodium sulfate (DSS)-induced colitis was used as the in vivo model, and tumor necrosis factor-α (TNFα)-stimulated HT-29 cells as the in vitro model. 1,8-cineole treatment significantly decreased the inflammatory response in DSS-induced colitis mice. 1,8-cineole treatment also increased nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into the nucleus to induce potent antioxidant effects. 1,8-cineole also increased colonic PPARγ protein expression. Similarly, 1,8-cineole decreased proinflammatory chemokine production and increased PPARγ protein expression in TNFα-stimulated HT-29 cells. 1,8-cineole also increased PPARγ promoter activity time-dependently. Because of its potent anti-inflammatory effects, 1,8-cineole may be valuable in treating IBD.

Sappanin-type homoisoflavonoids from Scilla nervosa inhibits acetylcholinesterase enzyme: a combined in silico and in vitro approach.

Alzheimer's disease is among the major health challenges that currently attract the attention of health care givers and drug discovery and development experts worldwide. This study investigated the acetylcholinesterase inhibitory activity of sappanin-type homisoflavonoids isolated from the inter-bulb surface of Scilla nervosa. Molecular docking, molecular dynamics simulation, ADMET and in vitro studies were performed to identify the hit molecules, understand their binding mode and interaction, druggability and establish their inhibitory potentials against acetylcholinesterase enzyme. The hit compounds 5, 2, 1 and 4 were identified as the hit molecules through the molecular docking. The molecular dynamics simulation and MM-PBSA analysis showed the hit homoisoflavonoids established stability and good binding affinity against the acetylcholinesterase enzyme. Also, 5 elicited the best inhibitory activity followed by 2, 1 and 4 in the in vitro experiment. Furthermore, the selected homoisoflavonoids exhibit interesting drug likeness and pharmacokinetic properties as drug candidate. The results suggest further investigations towards the development of the phytochemicals as possible acetylcholinesterase inhibitors.Communicated by Ramaswamy H. Sarma.

Immunoinformatics Approach to Design Novel Subunit Vaccine against the Epstein-Barr Virus.

Epstein-Barr virus (EBV) is a lymphotropic virus responsible for numerous epithelial and lymphoid cell malignancies, including gastric carcinoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and Burkitt lymphoma. Hundreds of thousands of people worldwide get infected with this virus, and in most cases, this viral infection leads to cancer. Although researchers are trying to develop potential vaccines and drug therapeutics, there is still no effective vaccine to combat this virus. In this study, the immunoinformatics approach was utilized to develop a potential multiepitope subunit vaccine against the two most common subtypes of EBV, targeting three of their virulent envelope glycoproteins. Eleven cytotoxic T lymphocyte (CTL) epitopes, 11 helper T lymphocyte (HTL) epitopes, and 10 B-cell lymphocyte (BCL) epitopes were predicted to be antigenic, nonallergenic, nontoxic, and fully conserved among the two subtypes, and nonhuman homologs were used for constructing the vaccine after much analysis. Later, further validation experiments, including molecular docking with different immune receptors (e.g., Toll-like receptors [TLRs]), molecular dynamics simulation analyses (including root means square deviation [RMSD], root mean square fluctuation [RMSF], radius of gyration [Rg], principal-component analysis [PCA], dynamic cross-correlation [DCC], definition of the secondary structure of proteins [DSSP], and Molecular Mechanics Poisson-Boltzmann Surface Area [MM-PBSA]), and immune simulation analyses generated promising results, ensuring the safe and stable response of the vaccine with specific immune receptors after potential administration within the human body. The vaccine's high binding affinity with TLRs was revealed in the docking study, and a very stable interaction throughout the simulation proved the potential high efficacy of the proposed vaccine. Further, in silico cloning was also conducted to design an efficient mass production strategy for future bulk industrial vaccine production. IMPORTANCE Epstein-Barr virus (EBV) vaccines have been developing for over 30 years, but polyphyletic and therapeutic vaccines have failed to get licensed. Our vaccine surpasses the limitations of many such vaccines and remains very promising, which is crucial because the infection rate is higher than most viral infections, affecting a whopping 90% of the adult population. One of the major identifications covers a holistic analysis of populations worldwide, giving us crucial information about its effectiveness for everyone's unique immunological system. We targeted three glycoproteins that enhance the virulence of the virus to design an epitope-based polyvalent vaccine against two different strains of EBV, type 1 and 2. Our methodology in this study is nonconventional yet swift to show effective results while designing vaccines.

α-Bisabolol Mitigates Colon Inflammation by Stimulating Colon PPAR-γ Transcription Factor: In Vivo and In Vitro Study.

The incidence and prevalence of inflammatory bowel disease (IBD, Crohn's disease, and ulcerative colitis) are increasing worldwide. The etiology of IBD is multifactorial, including genetic predisposition, dysregulated immune response, microbial dysbiosis, and environmental factors. However, many of the existing therapies are associated with marked side effects. Therefore, the development of new drugs for IBD treatment is an important area of investigation. Here, we investigated the anti-inflammatory effects of α-bisabolol, a naturally occurring monocyclic sesquiterpene alcohol present in many aromatic plants, in colonic inflammation. To address this, we used molecular docking and dynamic studies to understand how α-bisabolol interacts with PPAR-γ, which is highly expressed in the colonic epithelium: in vivo (mice) and in vitro (RAW264.7 macrophages and HT-29 colonic adenocarcinoma cells) models. The molecular docking and dynamic analysis revealed that α-bisabolol interacts with PPAR-γ, a nuclear receptor protein that is highly expressed in the colon epithelium. Treatment with α-bisabolol in DSS-administered mice significantly reduced Disease Activity Index (DAI), myeloperoxidase (MPO) activity, and colonic length and protected the microarchitecture of the colon. α-Bisabolol treatment also reduced the expression of proinflammatory cytokines (IL-6, IL1ß, TNF-α, and IL-17A) at the protein and mRNA levels. The expression of COX-2 and iNOS inflammatory mediators were reduced along with tissue nitrite levels. Furthermore, α-bisabolol decreased the phosphorylation of activated mitogen-activated protein kinase (MAPK) signaling and nuclear factor kappa B (NFκB) proteins and enhanced colon epithelial PPAR-γ transcription factor expression. However, the PPAR-α and ß/δ expression was not altered, indicating α-bisabolol is a specific stimulator of PPAR-γ. α-Bisabolol also increased the PPAR-γ transcription factor expression but not PPAR-α and ß/δ in pretreated in LPS-stimulated RAW264.7 macrophages. α-Bisabolol significantly decreased the expression of proinflammatory chemokines (CXCL-1 and IL-8) mRNA in HT-29 cells treated with TNF-α and HT-29 PPAR-γ promoter activity. These results demonstrate that α-bisabolol mitigates colonic inflammation by inhibiting MAPK signaling and stimulating PPAR-γ expression.