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Evaluation of therapeutic potentials of selected phytochemicals against Nipah virus, a multi-dimensional in silico study.

ABSTRACT: The current study attempted to evaluate the potential of fifty-three (53) natural compounds as Nipah virus attachment glycoprotein (NiV G) inhibitors through in silico molecular docking study. Pharmacophore alignment of the four (4) selected compounds (Naringin, Mulberrofuran B, Rutin and Quercetin 3-galactoside) through Principal Component Analysis (PCA) revealed that common pharmacophores, namely four H bond acceptors, one H bond donor and two aromatic groups were responsible for the residual interaction with the target protein. Out of these four compounds, Naringin was found to have the highest inhibitory potential ( - 9.19 kcal mol^-1) against the target protein NiV G, when compared to the control drug, Ribavirin ( - 6.95 kcal mol^-1). The molecular dynamic simulation revealed that Naringin could make a stable complex with the target protein in the near-native physiological condition. Finally, MM-PBSA (Molecular Mechanics-Poisson-Boltzmann Solvent-Accessible Surface Area) analysis in agreement with our molecular docking result, showed that Naringin ( - 218.664 kJ mol^-1) could strongly bind with the target protein NiV G than the control drug Ribavirin ( - 83.812 kJ mol^-1).

Supplementary information

The online version contains supplementary material available at 10.1007/s13205-023-03595-y.

SUBMITTER: Rababi D

PROVIDER: S-EPMC10170460 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Evaluation of therapeutic potentials of selected phytochemicals against Nipah virus, a multi-dimensional in silico study.

Rababi Deblina D Nag Anish A

3 Biotech 20230510 6

The current study attempted to evaluate the potential of fifty-three (53) natural compounds as Nipah virus attachment glycoprotein (NiV G) inhibitors through in silico molecular docking study. Pharmacophore alignment of the four (4) selected compounds (Naringin, Mulberrofuran B, Rutin and Quercetin 3-galactoside) through Principal Component Analysis (PCA) revealed that common pharmacophores, namely four H bond acceptors, one H bond donor and two aromatic groups were responsible for the residual ...[more]

PMID: 37180429

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Project description:BackgroundThe first emergence of the Nipah virus (NiV) in 1998 from Malaysia became a major concern when it came to light and resurfaced on different occasions thereafter. NiV is a bat-borne zoonotic and pleomorphic virus that causes severe infection in human and animal hosts. Studies revealed fruit bats are the major reservoirs as natural hosts and pigs as intermediate hosts for the spread of this infection. This became a major concern as the disease was characterized by high pathogenicity varying from 40% to 80% depending on its acuteness. Moreover, the solemnity lies in the fact that the infection transcends from being a mere mild illness to an acute respiratory infection leading to fatal encephalitis with a reportedly high mortality rate. Currently, there is no treatment or vaccine available against the NiV. Many antiviral drugs have been explored and developed but with limited efficacy.MethodologyIn search of high-affinity ayurvedic alternatives, we conducted a pan-proteome in silico exploration of the NiV proteins for their interaction with the best-suited phytoconstituents. The toxicity prediction of thirty phytochemicals based on their LD50 value identified thirteen potential candidates. Molecular docking studies of those thirteen phytochemicals with five important NiV proteins identified Tanshinone I as the potential compound with a high binding affinity.ResultsThe pharmacokinetics and pharmacodynamics studies also aided in determining the absorption, distribution, metabolism, excretion, and toxicity of the selected phytoconstituent. Interestingly, docking studies also revealed Rosmariquinone as a potent alternative to the antiviral drug Remdesivir binding the same pocket of RNA-dependent RNA polymerase of the NiV. A molecular dynamics simulation study of the surface glycoprotein of NiV against Tanshinone I showed a stable complex formation and significant allosteric changes in the protein structure, implying that these phytochemicals could be a natural alternative to synthetic drugs against NiV.ConclusionThis study provides preliminary evidence based on in silico analysis that the herbal molecules showed an effect against NiV. However, it is essential to further evaluate the efficacy of this approach through cell-based experiments, organoid models, and eventually clinical trials.

Project description:The SARS-Cov-2 virus, which is evolving continuously and causing adverse effects throughout the world, needs an effective drug molecule for its treatment. There are several receptors of SARS Cov-2 which are targeted for its inhibition by many lead molecules both in-vitro and in-vivo. Papain like Protease (PLpro) is one of the two SARS-Cov-2 proteases that can be used as a drug target for SARS Cov-2. It is a coronavirus enzyme that plays a role in the cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex and disruption of host responses. PLpro has also been linked to the cleavage of proteinaceous post translational modifications on host proteins as a means of evading antiviral immune responses. Structure-based drug discovery can be one of the effective methods to screen for various molecules against the target receptors. In this study, PLpro of SARS CoV-2 was chosen as the target for docking. Forty phytochemicals from various plant sources and four synthetic drugs have been screened for their inhibitory potential against PLpro using AutoDock Vina. Phytochemicals such as Tinosponone, Rhoifolin, Rosmanol, Berberin, Nimbin and two other existing drugs Elbasvir and Declatasvir showed higher inhibitory potential in terms of higher binding affinities. ADME and toxicity analysis were also performed to predict the pharmacokinetics and drug likeliness properties. It was concluded from the study that Tinosponone possesss potential inhibitor property of papain-like proteases (PLpro) of SARS CoV-2. Tinosponone from the plant Tinospora cordifolia had a binding affinity of - 9.3 kcal/mol and obeyed the Lipinski rules, making it an effective lead molecule for treating SARS CoV-2. Molecular Dynamics simulation of Tinosponone with PLpro has proved the stability and validity of the binding with RMSD value in range of 0.2 nm when it was run for 50 ns using GROMACS. Therefore, Tinosponone could be considered as a potential inhibitor of PLpro of SARS CoV-2.

Project description:The resurgence of the Nipah virus (NiV) in 2023 has raised concerns for another potentially severe pandemic, given its history of high mortality from previous outbreaks. Unfortunately, no therapeutics and vaccines have been available for the virus. This study used immunoinformatics and molecular modeling to design and evaluate a multi-epitope subunit vaccine targeting NiV. The designed vaccine construct aims to stimulate immune responses in humans and two other intermediate animal hosts of the virus-swine and equine. Using several epitope prediction tools, ten peptides that induced B-lymphocyte responses, 17 peptides that induced cytotoxic T-lymphocyte (CTL) responses, and 12 peptides that induced helper T-lymphocyte (HTL) responses were mapped from nine NiV protein sequences. However, the CTL and HTL-inducing peptides were reduced to ten and eight, respectively, following molecular docking and dynamics. These screened peptides exhibited stability with 30 common major histocompatibility complex (MHC) receptors found in humans, swine, and equine. All peptides were linked using peptide linkers to form the multi-epitope construct and various adjuvants were tested to enhance its immunogenicity. The vaccine construct with resuscitation-promoting factor E (RpfE) adjuvant was selected as the final design based on its favorable physicochemical properties and superior immune response profile. Molecular docking was used to visualize the interaction of the vaccine to toll-like receptor 4 (TLR4), while molecular dynamics confirmed the structural stability of this interaction. Physicochemical property evaluation and computational simulations showed that the designed vaccine construct exhibited favorable properties and elicited higher antibody titers than the six multi-epitope NiV vaccine designs available in the literature. Further in vivo and in vitro experiments are necessary to validate the immunogenicity conferred by the designed vaccine construct and its epitope components. This study demonstrates the capability of computational methodologies in rational vaccine design and highlights the potential of cross-species vaccination strategies for mitigating potential NiV threats.

Project description:Abstract Objectives Herbs and spices (H/S) are rich sources of bioactive compounds with a limited understanding of their absorption and metabolism in humans. This study aimed to characterize H/S metabolites in human plasma samples over 24 h after H/S intake. Methods Plasma samples from a randomized, single-blinded, 4-arm, 24-h, crossover clinical trial (Clincaltrials.gov NCT03926442) were used for this research. Subjects (n = 24, aged 37 ± 3 years, BMI = 28.4 ± 0.6 kg/m2) consumed a high-fat/high-carbohydrate meal with salt and pepper only (control) or with three different H/S mixtures: Italian herbs (rosemary, basil, thyme, oregano, and parsley), cinnamon, and pumpkin pie spice (cinnamon, ginger, nutmeg, and allspice), and blood samples were collected at 0, 0.5, 1, 2, 4, 5.5, 7 and 24 h. Meals contained 1 g H/S per 135 kcal and delivered 35% of each subject's energy needed to maintain weight. Quantitative analysis of H/S metabolites was conducted using UHPLC-QQQ based on reference standards and reported multiple reaction monitoring transitions. Results We have tentatively identified 58 metabolites in plasma samples, including 32 phenolic acids, 11 terpenoids, 6 flavonoids, and 9 other polyphenol metabolites. Preliminary analysis (n = 13) showed that coumarin glucuronide increased after cinnamon and pumpkin pie meals and peaked at 2 h (2656.8 ± 481.3 nmol/L and 1542 ± 275.7 nmol/L respectively), and returned to baseline concentration at 24 h. After consuming Italian herbs meal, carnosol appeared in plasma early peaking at 1 h (48.2 ± 7.0 nmol/L); carnosic acid and 12-methoxy carnosic acid peaked at 2 h (366.4 ± 142.2 nmol/L and 588.6 ± 66.3nmol/L, respectively), and these metabolites circulated in the body for up to 24 h; apigenin-7-O-glucuronide peaked at 7 h (6.0 ± 1.7 nmol/L); carnosic acid glucuronide peaked at 24 h (510.9 ± 86 nmol/L). 6- and 10-gingerol glucuronide peaked at 1 h and 2 h after consuming pumpkin pie meal (1.4 ± 0.6 nmol/L and 6.7 ± 1.7 nmol/L), and returned to baseline concentration at 5.5 and 7 h, respectively. All data are expressed as mean ± SEM. Conclusions H/S bioactive compounds are absorbed and metabolized in the human body to early and late phase metabolites, peaking at various time-points across 24 h in response to different H/S meals. Funding Sources This project was supported by a gift from McCormick Science Institute and various donor funds.

Project description:BackgroundIn the wake of emergence of antimicrobial resistance, bioactive phytochemical compounds are proving to be important therapeutic agents. The present study envisaged in silico molecular docking as well as in vitro antimicrobial efficacy screening of identified phytochemical ligands to the dispersin (aap) and outer membrane osmoporin (OmpC) domains of enteroaggregative Escherichia coli (EAEC) and non-typhoidal Salmonella spp. (NTS), respectively.Materials and methodsThe evaluation of drug-likeness, molecular properties, and bioactivity of the identified phytocompounds (thymol, carvacrol, and cinnamaldehyde) was carried out using Swiss ADME, while Protox-II and StopTox servers were used to identify its toxicity. The in silico molecular docking of the phytochemical ligands with the protein motifs of dispersin (PDB ID: 2jvu) and outer membrane osmoporin (PDB ID: 3uu2) were carried out using AutoDock v.4.20. Further, the antimicrobial efficacy of these compounds against multi-drug resistant EAEC and NTS strains was determined by estimating the minimum inhibitory concentrations and minimum bactericidal concentrations. Subsequently, these phytochemicals were subjected to their safety (sheep and human erythrocytic haemolysis) as well as stability (cationic salts, and pH) assays.ResultsAll the three identified phytochemicals ligands were found to be zero violators of Lipinski's rule of five and exhibited drug-likeness. The compounds tested were categorized as toxicity class-4 by Protox-II and were found to be non- cardiotoxic by StopTox. The docking studies employing 3D model of dispersin and ompC motifs with the identified phytochemical ligands exhibited good binding affinity. The identified phytochemical compounds were observed to be comparatively stable at different conditions (cationic salts, and pH); however, a concentration-dependent increase in the haemolytic assay was observed against sheep as well as human erythrocytes.ConclusionsIn silico molecular docking studies provided useful insights to understand the interaction of phytochemical ligands with protein motifs of pathogen and should be used routinely before the wet screening of any phytochemicals for their antibacterial, stability, and safety aspects.

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Evaluation of therapeutic potentials of selected phytochemicals against Nipah virus, a multi-dimensional in silico study.

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Evaluation of therapeutic potentials of selected phytochemicals against Nipah virus, a multi-dimensional in silico study.

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