Molecular Docking Interaction Research Articles

Molluscicidal activity of sodium hypochlorite against Biomphlaria alexandrina snails: Immunological and hepato-endocrine alterations with in silico docking study

Schistosomiasis is a tropical disease that widely neglected. Schistosoma mansoni reproduce asexually within the freshwater snail, Biomphlaria alexandrina. Sodium hypochlorite (NaOCl) is a widely used disinfectant, so its effect against gainst B. alexandrina snails was evaluated. The present results showed that NaOCl has a molluscicidal activity against adult B. alexandrina snails at LC50 1.25 ppm. Hemocytes displayed varied morphological forms after being exposed to the LC10 and LC25 concentrations of NaOCl in B. alexandrina snails, and the phagocytic index of B. alexandrina snail's hemocytes significantly increased. The phagocytic potency of exposed hemocytes to charcoal showed ruptured plasma membrane, engulfed particles, vacuolation in the cytoplasm and degeneration of nuclei. When B. alexandrina snails were treated with sublethal concentrations of NaOCl, transaminases (AST & ALT), alkaline and acid phosphatase activities were significantly increased. In contrast, the total protein, albumin concentrations, Testosterone (T) and 17β Estradiol (E) showed a significant decrease (p ≤ 0.05) as compared to the control groups. The molecular docking interaction showed high efficiency for the ligand, NaOCl against the receptor binding sites of the acid phosphatase, alanine aminotransferase, estrogen and testosterone. The present results showed that NaOCl could be used as an effective molluscicide against B. alexandrina snails but more attention should be paid to investigate the side effects on the non-target organisms living in the freshwater environment.

The utilization of natural eco-benign sources for sustainable management to preserve hides and docking analysis of identified potential phytochemicals.

The industrial leather sector is one of the most ancient industries globally and continues to influence the global economic system in contemporary times significantly. Regardless of income, the leather sector is widely recognized as a significant environmentally detrimental sector because of the utilization of materials involved in preserving and processing leather. Raw hides, the primary ingredient in the leather industry, are highly susceptible to microbial attack once they have been flayed from animals. The current review provides information about the diverse operational processes employed in the beam house to produce leather goods. This paper primarily focuses on the preservation of various types of hides, including those derived from goats, cows, sheeps, deers, pigs, and other species, with particular emphasis on bio-based preservation methods. It also discusses various salt and salt-free curing methods along with their limitations. Furthermore, it reviews a viable and economically advantageous option for preserving animal hides using plant and microbial sources. Moreover, it focuses on investigating the molecular docking interactions between three critical enzymes in the phytochemical synthesis pathway, namely phenylalanine ammonia-lyase, phosphomevalonate kinase, and dihydroflavonol 4-reductase, and a set of specific modulators, followed by ADMET analyses. The objective was to determine the optimal binding affinity score for these enzyme-modulator complexes through virtual screening. The depiction of protein-ligand interactions offers potential benefits for future research endeavours, as well as valuable insights into the identification of modulators and the evaluation of the potency and efficacy of phytochemicals in the preservation of hides.

Pseudomonas putida Metallothionein: Structural Analysis and Implications of Sustainable Heavy Metal Detoxification in Madinah.

Heavy metals, specifically cadmium (Cd) and lead (Pb), contaminating water bodies of Madinah (Saudi Arabia), is a significant environmental concern that necessitates prompt action. Madinah is exposed to toxic metals from multiple sources, such as tobacco, fresh and canned foods, and industrial activities. This influx of toxic metals presents potential hazards to both human health and the surrounding environment. The aim of this study is to explore the viability of utilizing metallothionein from Pseudomonas putida (P. putida) as a method of bioremediation to mitigate the deleterious effects of pollution attributable to Pb and Cd. The use of various computational approaches, such as physicochemical assessments, structural modeling, molecular docking, and protein-protein interaction investigations, has enabled us to successfully identify the exceptional metal-binding properties that metallothionein displays in P. putida. The identification of specific amino acid residues, namely GLU30 and GLN21, is crucial in understanding their pivotal role in facilitating the coordination of lead and cadmium. In addition, post-translational modifications present opportunities for augmenting the capacity to bind metals, thereby creating possibilities for focused engineering. The intricate web of interactions among proteins serves to emphasize the protein's participation in essential cellular mechanisms, thereby emphasizing its potential contributions to detoxification pathways. The present study establishes a strong basis for forthcoming experimental inquiries, offering potential novel approaches in bioremediation to tackle the issue of heavy metal contamination. Metallothionein from P. putida presents a highly encouraging potential as a viable remedy for environmental remediation, as it is capable of proficiently alleviating the detrimental consequences related to heavy metal pollution.

Exploration of the main active metabolites from Tinospora crispa (L.) Hook. f. & Thomson stem as insulin sensitizer in L6.C11 skeletal muscle cell by integrating in vitro, metabolomics, and molecular docking

Ethnopharmacological relevanceTinospora crispa (L.) Hook. f. & Thomson stem (TCS) has long been used as folk medicine for the treatment of diabetes mellitus. Previous study revealed that TCS possesses multi-ingredients and multi-targets characteristic potential as insulin sensitizer activity. However, its mechanisms of action and molecular targets are still obscure. Aim of the studyIn the present study, we investigated the effects of TCS against insulin resistance in muscle cells through integrating in vitro experiment and identifying its active biomarker using metabolomics and in molecular docking validation. Materials and methodsWe used centrifugal partition chromatography (CPC) to isolate 33 fractions from methanolic extract of TCS, and then used UHPLC-Orbitrap-HRMS to identify the detectable metabolites in each fraction. We assessed the insulin sensitization activity of each fraction using enzyme-linked immunosorbent assay (ELISA), and then used confocal immunocytochemistry microscopy to measure the translocation of glucose transporter 4 (GLUT4) to the cell membrane. The identified active metabolites were further simulated for its molecular docking interaction using Autodock Tools. ResultsThe polar fractions of TCS significantly increased insulin sensitivity, as measured by the inhibition of phosphorylated insulin receptor substrate-1 (pIRS1) at serine-312 residue (ser312) also the increasing number of translocated GLUT4 and glycogen content. We identified 58 metabolites of TCS, including glycosides, flavonoids, alkaloids, coumarins, and nucleotides groups. The metabolomics and molecular docking simulations showed the presence of minor metabolites consisting of tinoscorside D, higenamine, and tinoscorside A as the active compounds. ConclusionsOur findings suggest that TCS is a promising new treatment for insulin resistance and the identification of the active metabolites in TCS could lead to the development of new drugs therapies for diabetes that target these pathways.

Anti-quorum Sensing and Anti-biofilm Effect of Nocardiopsis synnemataformans RMN 4 (MN061002) Compound 2,6-Di-tert-butyl, 1,4-Benzoquinone Against Biofilm-Producing Bacteria.

In this study, the anti-biofilm compound of 2,6-Di-tert-butyl, 1,4-benzoquinone was purified from Nocardiopsis synnemataformans (N. synnemataformans) RMN 4 (MN061002). To confirm the compound, various spectroscopy analyses were done including ultraviolet (UV) spectrometer, Fourier transform infrared spectroscopy (FTIR), analytical high-performance liquid chromatography (HPLC), preparative HPLC, gas chromatography-mass spectroscopy (GC-MS), liquid chromatography-mass spectroscopy (LC-MS), and 2D nuclear magnetic resonance (NMR). Furthermore, the purified compound was shown 94% inhibition against biofilm-producing Proteus mirabilis (P. mirabilis) (MN396686) at 70µg/mL concentrations. Furthermore, the metabolic activity, exopolysaccharide damage, and hydrophobicity degradation results of identified compound exhibited excellent inhibition at 100µg/mL concentration. Furthermore, the confocal laser scanning electron microscope (CLSM) and scanning electron microscope (SEM) results were shown with intracellular damages and architectural changes in bacteria. Consecutively, the in vivo toxicity effect of the compound against Artemia franciscana (A. franciscana) was shown to have a low mortality rate at 100µg/mL. Finally, the molecular docking interaction between the quorum sensing (QS) genes and identified compound clearly suggested that the identified compound 2,6-Di-tert-butyl, 1,4-benzoquinone has anti-quorum sensing and anti-biofilm activities against P. mirabilis (MN396686).

Molecular Docking, ADMET Analysis and Molecular Dynamics (MD) Simulation to Identify Synthetic Isoquinolines as Potential Inhibitors of SARS-CoV-2 MPRO.

The rapidly widespread SARS-CoV-2 infection has affected millions worldwide, thus becoming a global health emergency. Although vaccines are already available, there are still new COVID-19 cases daily worldwide, mainly due to low immunization coverage and the advent of new strains. Therefore, there is an utmost need for the discovery of lead compounds to treat COVID-19. Considering the relevance of the SARS-CoV-2 MPRO in viral replication and the role of the isoquinoline moiety as a core part of several biologically relevant compounds, this study aimed to identify isoquinoline-based molecules as new drug-like compounds, aiming to develop an effective coronavirus inhibitor. 274 isoquinoline derivatives were submitted to molecular docking interactions with SARS-CoV-2 MPRO (PDB ID: 7L0D) and drug-likeness analysis. The five best-docked isoquinoline derivatives that did not violate any of Lipinski's or Veber's parameters were submitted to ADMET analysis and molecular dynamics (MD) simulations. The selected compounds exhibited docking scores similar to or better than chloroquine and other isoquinolines previously reported. The fact that the compounds interact with residues that are pivotal for the enzyme's catalytic activity, and show the potential to be orally administered makes them promising drugs for treating COVID-19. Ultimately, MD simulation was performed to verify ligand-protein complex stability during the simulation period.

Initiation of Apoptotic Pathway by the Cell-Free Supernatant Synthesized from Weissella cibaria Through In-Silico and In-Vitro Methods.

Globally, colorectal cancer is the most prevalent type of cancer. Even though multiple treatments such as surgery, radiation, chemotherapy, and immunotherapy are available, the adverse effects caused in patients seem remarkable. Therefore, the current work was deliberated to prepare the metabolites (cell-free supernatant-CFS) from Weissella cibaria RK-3-1 to conduct in-silico and in-vitro-based anticancer assays. First, the active biomolecules present in the CFS were screened using a GC-MS analyzer. In addition, in-silico-based pharmacokinetic and docking studies were performed to confirm the anticancer potential of metabolites. In-silico results suggested that the bioactive compounds such as filicinic acid, dibutyl phthalate, and 4H-pyran-4-one,2,3-dihydro-3,5-dihydroxy-6-methyl present in CFS possessed significant molecular docking interactions with anticancer hub proteins. Furthermore, in-vitro results displayed the inhibition of cell proliferation in HT-29 cells at an IC50 value of 22.5 ± 1.3µg/ml with the least significant effect on HEK-293 cell lines. Moreover, bacterial metabolites-controlled cell proliferation during the cell cycle's synthesis phase (S). Furthermore, the gene expression results confirm the increased expression of Bad, Bax, Bcl2, caspase-3, and cytochrome-C genes involved in the intrinsic apoptotic pathway. Hence, our findings from the in-silico and the in-vitro study confirm the anticancer potential of cell free-supernatant synthesized by W. cibaria.

‘In silico’ repurposing new inhibitors of EGFR and VEGFR-2 kinases via biophysical mechanisms

Epidermal growth factor receptor (EGFR) controls cell growth, death, and proliferation through a variety of signaling mechanisms. The expression of vascular endothelial growth factor receptor-2 (VEGFR-2) by endothelial cells from malignant tissues triggers a series of signaling pathways that lead to tumor angiogenesis and increase cancer cell survival, proliferation, migration, and vascular permeability. The aim is to find novel inhibitors for EGFR and VEGFR-2 kinases by molecular docking drug-likeness models, pharmacokinetic, interaction analysis, and molecular dynamic simulation. Over 482 ligands were tested against the kinases, there are about 20 compounds that had the best docking scores for the 2 kinases but only compound 2C inhibited them with the highest score values by binding to active sites pocket established through molecular docking study. Secondly, the drug-likeness score of 2C was very good compared to the other compounds. The pharmacokinetics, physicochemical properties, and toxicity of 2C were much better than sorafenib and erlotinib as references. Analysis of interaction showed a strong interaction between 2C and active sites of EGFR and VEGFR-2 kinases illustrated by calculation of halogen bonds, π-Cation Interactions, Hydrogen Bonds, and Hydrophobic Interactions. Finally, the molecular dynamic simulation was also used to assess the stability of the EGFR and VEGFR-2 kinases-2C complexes. The complexes’ stability was validated by RMSD, Rg , RMSF, SASA, and several hydrogen bonds analysis. 2C was shown to interact stably with pocket residues after MD simulation. Compound 2C may be a promising way to slow the signaling cascade of proteins that are significant contributors to the spread of cancer. Communicated by Ramaswamy H. Sarma

In Silico Assessment of the Role of Iridoid in the Treatment of Zika and Influenza Virus Infection

Iridoids have been showing anticancer, antiproliferative, cardioprotective, hepatoprotective, antihyperglycemic, and immune stimulatory activities. Zika and H3N2 viruses belong to the RNA virus category, which was responsible for the reoccurrence of epidemics and pandemics in the last decades. Both infections are the type of zoonotic diseases that transmit very fast. In this manuscript, we selected 59 iridoids (iridoid glycosides, secoiridoids, bis-iridoids, and non-glycosidic iridoids) and performed molecular docking (MD) interaction studies against PDB ID: 7VLG (Zika virus receptor) and PDB ID: 6EUY (H3N2 influenza virus receptor). MD interaction revealed that 2'-O-(4-methoxycinnamoyl) mussaenosidic acid and 6-O-trans-p-Coumaroyl–8-O-acetylshanzhiside methyl ester showed a maximum dock score of –8.6 kcal/mol and –9.2 kcal/mol against PDB ID: 7VLG and PDB ID: 6EUY, respectively. The MD interaction data was confirmed by MD simulation and MMPBSA analysis. MD simulation data showed that RMSD and RMSF were within the limit. MM/PBSA analysis data showed that free binding energy of –21.398 kJ/mol and –127.169 kJ/mol observed with 2'-O-(4-methoxycinnamoyl) mussaenosidic acid–7VLGand 6-O-trans-p-Coumaroyl–8-O-acetylshanzhiside methyl ester–6EUY, respectively. ADMET studies showed that both the final molecules were nontoxic in nature, but they required modification during formulation development. These data confirmed that if we reroute these iridoids toward Zika virus and influenza (H3N2) strains, it will be beneficial for mankind.

Complement System Inhibitory Drugs in a Zebrafish (Danio rerio) Model: Computational Modeling.

The dysregulation of complement system activation usually results in acute or chronic inflammation and can contribute to the development of various diseases. Although the activation of complement pathways is essential for innate defense, exacerbated activity of this system may be harmful to the host. Thus, drugs with the potential to inhibit the activation of the complement system may be important tools in therapy for diseases associated with complement system activation. The synthetic peptides Cp40 and PMX205 can be highlighted in this regard, given that they selectively inhibit the C3 and block the C5a receptor (C5aR1), respectively. The zebrafish (Danio rerio) is a robust model for studying the complement system. The aim of the present study was to use in silico computational modeling to investigate the hypothesis that these complement system inhibitor peptides interact with their target molecules in zebrafish, for subsequent in vivo validation. For this, we analyzed molecular docking interactions between peptides and target molecules. Our study demonstrated that Cp40 and the cyclic peptide PMX205 have positive interactions with their respective zebrafish targets, thus suggesting that zebrafish can be used as an animal model for therapeutic studies on these inhibitors.

Experimental and in silico evaluation of Carthamus tinctorius L. oil emulgel: a promising treatment for bacterial skin infections.

The current study aimed to develop a topical herbal emulgel containing Carthamus tinctorius L. (CT) oil extract, which has been scientifically proven for its antibacterial and antioxidant activities for the ailment of bacterial skin infections. The CT emulgel was formulated by response surface methodology (RSM) and was evaluated by various parameters like extrudability, spreadability, pH, viscosity, and antibacterial and antioxidant activities. Molecular docking was also performed using AutoDock. Among all formulated CT emulgels, F9 and F8 were optimized. Optimized formulations had shown good spreadability and extrudability characteristics. Sample F8 had % inhibition of 42.131 ± 0.335, 56.720 ± 0.222, and 72.440 ± 0.335 at different concentrations. Sample F9 had % inhibition of 26.312 ± 0.280, 32.461 ± 0.328, and 42.762 ± 0.398 at concentrations of 250 µg/ml, 500 µg/ml, and 1,000 µg/ml, respectively, which shows that both samples F8 and F9 have significant antioxidant potential. Optimized CT emulgels F8 and F9 had significant antibacterial activity against Staphylococcus aureus and Escherichia coli at p-value = 0.00, the Emulgel-F8 shows zone of inhibition of 24 mm for E-coli and 19 mm for S-aureus. Emulgel-F9 shows zone of inhibition of 22 mm for E-coli and 15 mm for S-aureus while pure CT- Oil extract shows zone of inhibition of 25 mm for E-coli and 20 mm for S-aureus and ciprofloxacin used as standard shows 36mm zone of inhibition against both E-coli and S-aureus. The comparative investigation through molecular docking binding affinities and interactions of ligands with various target proteins provides insights into the molecular processes behind ligand binding and may have significance for drug discovery and design for the current study. The current study suggests that C. tinctorius L.-based emulgel has good antioxidant and antibacterial activities against E. coli for the treatment of bacterial skin infections.

Synthesis, Antioxidant, Molecular Docking and DNA Interaction Studies of Metal-Based Imine Derivatives.

Currently, numerous ongoing studies are investigating the interaction of free radicals with biological systems, such as lipids, DNA and protein. In the present work, synthesis, characterization, antioxidant, DNA binding and molecular docking studies of Schiff base ligand and its Ni(II), Co(II), Cu(II) and Zn(II) were evaluated. The metal complexes have shown significant dose-dependent antioxidant activities higher than those of the free ligand but lesser than those of the standard antioxidant, ascorbic acid. The DNA binding constants (Kb) were found in the order Zn(pimp)2 {9.118 × 105 M-1} > H-pimp {3.487 × 105 M-1} > Co(pimp)2 {3.090 × 105 M-1} > Ni(pimp)2 {1.858 × 105 M-1} > Cu(pimp)2 {1.367 × 105 M-1}. Binding constants (Kb) values calculated from the molecular docking analysis were found to be in close agreement with the experimental results. The obtained results indicate the importance of synthesis complexes as a source of synthetic antioxidants and anticancer drugs.

Chemical profiling and biological activities of Dipterygium glaucum Decne.: An in-vivo, in-vitro and in-silico evaluation

Dipterygium glaucum Decne. is a desert plant with medicinal significance used traditionally in treating bronchial asthma. This study investigated the phytochemical composition, toxicity, antioxidant, anti-inflammatory, antidiabetic and anti-Alzheimer potential of the ethanolic extract of D. glaucum (DGEE). The chemical composition showed that the extract is rich in TPC (119.56 ± 1.23 GAE/g) and TFC (53.29 ± 3.21 QE/g) with 31 compounds detected in GC-MS analysis. The acute toxicity study revealed the safety of the extract with no significant difference in physical, biochemical, hematological parameters and the weight of the vital organs at 300 mg/kg B.W. of day-old chicks. The anti-inflammatory evaluation presented a significant (p < 0.001) anti-inflammatory effect compared to the standard dexamethasone. Similarly, in in vitro antidiabetic evaluation, the extract showed inhibitory potential against α-glucosidase with an IC50 value of (18.24 ± 0.05 µg/ mL) and anti-Alzheimer potential by inhibiting acetylcholinesterase with an IC50 value of (39.65 ± 0.08 µg/ mL). The in vitro antioxidant capacity determination of DGEE presented strong activity with the highest (47.27 ± 0.07 mg TE/g) in the DPPH method. The in-silico studies of the selected compounds from the GC-MS profile showed good molecular docking interaction against α-glucosidase and acetylcholinesterase. Similarly, the in silico computational approach was applied to study the interaction of the compounds with antioxidant enzymes and nitric oxide synthase. Overall, the results revealed that the extract is safe for use and it exerts pharmacological effects through the antioxidant-based mechanisms and warrants further research on its toxicity and in vivo pharmacological profile.

Antibacterial mechanism of action and in silico molecular docking studies of Cupressus funebris essential oil against drug resistant bacterial strains

The primary objective of this research work was to study the antibacterial effects of Cupressus funebris essential oil (EO) against various drug resistant bacterial pathogens along with studying the molecular docking interactions of the major components of the EO with the key bacterial proteins/enzymes. Gas chromatography-mass spectrometry was used to analyse the chemical composition of the Cupressus funebris EO. The initial antibacterial screening was performed by using disc diffusion and microdilution methods. Scanning electron microscopy was also performed in order to study effects of the EO on bacterial cell morphology. Further, molecular docking studies were performed using Autodock Vina and results were visualised by BIOVIA Discovery Studio. The chemical composition of the EO showed the presence of 15 components with citronellal, terpinene-4-ol, α-phellandrene and 1,8-cineole as the major components of the EO. Results indicated that the EO of Cupressus funebris exhibited dose-dependent as well as time dependent antibacterial effects. The scanning electron microscopy indicated that the Cupressus funebris EO led to membrane rupture and permeabilization of the bacterial cells. Molecular docking studies indicated that the major compounds of the EO (citronellal and terpinene-4ol) showed strong interactions with the active site of the bacterial DNA gyrase enzyme explaining the antibacterial mode of action of the EO. Ciprofloxacin was also used for docking which showed stronger interactions with the target protein than citronellal or terpinene-4-ol. In conclusion, the major findings of the current study were that the EO of Cupressus funebris causes bacterial membrane rupture and permeabilization, shows time-dependent and dose-dependent antibacterial action, along with interacting with crucial bacterial enzyme viz., DNA gyrase as indicated by molecular docking studies.

Exploration of selected monoterpenes as potential TRPC channel family modulator in lung cancer, an in-silico upshot

Lung cancer is still the most frequent cause of cancer-related death, accounting for nearly two million cases yearly. As cancer is a multifactorial disease, developing novel molecular therapeutics that can simultaneously target multiple associated cellular processes has become necessary. Ion channels are diverse regulators of cancer-related processes such as abnormal proliferation, invasion, migration, tumor progression, inhibition of apoptosis, and chemoresistance. Among the various families of ion channels, the transient receptor potential canonical channel family steps out in the context of lung cancer, as several members have been postulated as prognostic markers for lung cancer. Phytochemicals have been found to have health benefits in the treatment of a variety of diseases and disorders. Among phytochemicals, monoterpenes are effective in treating both the early and late stages of cancer. The molecular docking interaction analysis was conducted to evaluate the binding potential of selected monoterpenes with TRPC3, TRPC4, TRPC5, and TRPC6 involved in different phases of carcinogenesis. Amongst the selected monoterpenes, thymoquinone exhibited the highest binding energy of −6.7 kcal/mol against the TRPC4 channel, and all amino acid binding residues were similar to those of the known inhibitor for TRPC4. In addition, molecular-dynamic simulation results parameters, such as RMSD, RMSF, and Rg, indicated that thymoquinone did not impact the protein compactness and exhibited stability during the interaction. The average interaction energy between thymoquinone and TRPC4 protein was −26.85 kJ/mol. In-silico Drug-likeness and ADMET profiling indicated that thymoquinone is a druggable candidate with minimal toxicity. We propose further investigation and evaluation of thymoquinone for lead optimization and drug development. Communicated by Ramaswamy H. Sarma

Phytoconstituents from Urtica dioica (stinging nettle) of Sikkim Himalaya and their molecular docking interactions revealed their nutraceutical potential as α-amylase and α-glucosidase inhibitors.

In this study, antioxidative methanolic leaf extract (MeOH-SIS) of Urtica dioica was characterized for anti-diabetic activity. The extract was purified on a column to yield seven homogenous fractions (F1-F7) which were further determined for DPPH radical scavenging activity. MeOH-SIS and the fraction F1 (selected based on % yield and activity) were evaluated for their in vitro α-amylase and α-glucosidase inhibitory activity. The results showed inhibition of both enzymes in a dose dependent manner and F1 exhibited relatively higher inhibition than its mother extract MeOH-SIS. GC-MS analyses of both the extracts identified 24 major compounds among which 10 were previously described as bioactive compounds. Among all, 5 compounds demonstrated to have quality pharmacokinetics profiles and were examined for possible binding affinity against the active sites of α-amylase and α-glucosidase using molecular docking. The binding interaction of 2R-acetoxymethyl-1,3,3-trimethyl-4T-(3-methyl-2-buten-1-yl)-1T-cyclohexanol within the active sites of the target receptors was found to be significant among others, and can be developed as a potential inhibitor of α-amylase and α-glucosidase. The leaf extract can be utilized to develop food additive for the control and management of oxidative stress induced diabetes.

Insight into Jasminum sambac Molecular Docking Interaction with GCK related to Diabetes Mellitus

Insight into Jasminum sambac Molecular Docking Interaction with GCK related to Diabetes Mellitus

Translational and structural vaccinomics approach to design a multi-epitope vaccine against NOL4 autologous antigen of small cell lung cancer.

Small cell lung cancer (SCLC) is one of the most common cancers and it is the sixth common cause for cancer-related deaths. The high plasticity and metastasis have been a major challenge for humanity to treat the disease. Hence, a vaccine for SCLC has become an urgent need of the hour due to public health concern. Implementation of immunoinformatics technique is one of the best way to find a suitable vaccine candidate. Immunoinformatics tools can be used to overcome the limitations and difficulties of traditional vaccinological techniques. Multi-epitope cancer vaccines have become a next-generation technique in vaccinology which can be used to stimulate more potent immune response against a particular antigen by eliminating undesirable molecules. In this study, we used multiple computational and immunoinformatics approach to design a novel multi-epitope vaccine for small cell lung cancer. Nucleolar protein 4 (NOL4) is an autologous cancer-testis antigen overexpressed in SCLC cells. Seventy-five percent humoral immunity have been identified for this particular antigen. In this study, we mapped immunogenic cytotoxic T lymphocyte, helper T lymphocyte, and interferon-gamma epitopes present in NOL4 antigen and designed a multi-epitope-based vaccine using the predicted epitopes. The designed vaccine was antigenic, non-allergenic, and non-toxic with 100% applicability on human population. The chimeric vaccine construct showed stable and significant interaction with endosomal and plasmalemmal toll-like receptors in molecular docking and protein-peptide interaction analysis, thus assuring a strong potent immune response against the vaccine upon administration. Therefore, these preliminary results can be used to carry out further experimental investigations.

An Evidence of Drug Repurposing for COVID-19 Pandemic Based on &lt;i&gt;In silico&lt;/i&gt; Investigation from Phenolic Derivatives of Silybum Marianum Against SARS-Cov-2 Proteins

The outbreak of coronavirus disease-2019 (COVID-19) had a striking impact on the worldwide healthcare system within a very short period. The availability of a large number of clinical data on SARS-CoV-2, conventional precautionary majors, and treatment strategies with the existing therapeutic antiviral drug molecules also fails to control progression and disease transmission among the population. Hence, we implemented pharmacoinformatics approaches to facilitate the drug discovery by repurposing naturally available therapeutic molecules as an effective intervention. The major phenolic derivatives of &lt;em&gt;Silybum marianum &lt;/em&gt;(Milk thistle) have been identified and investigated for ADME (Absorption, Distribution, Metabolism and Excretion)/tox properties. Co-crystallized structure of three major proteins (i.e., main protease, RNA binding domain of nucleocapsid phosphoprotein and Spike receptor binding domain) from SARS-CoV-2 investigated with molecular docking (MD) interaction with the phenolic compounds from milk thistle. Furthermore, a 100 ns MD simulation was performed with silibinin molecule based on ADMET and MD interaction. Being less toxic in ADME, a good MD interaction and stability of silibinin molecule across the MD simulation trajectories with targeted proteins explicate that silibinin molecule can be a promising drug candidate against the main protease and will be helpful to cease the enzymatic activity in viral replication and transcription.

Naringin from Coffee Inhibits Foodborne Aspergillus fumigatus via the NDK Pathway: Evidence from an In Silico Study

In the tropics, coffee has been one of the most extensively cultivated economic crops, especially Arabica coffee (Coffea arabica L.). The coffee pulp, which includes phytochemicals with a proven antifungal action, is one of the most insufficiently utilized and neglected byproducts of coffee refining. In the current experiment, we carried out in silico screening of the isolated Arabica coffee phytochemicals for antifungal activity against Aspergillus fumigatus: a foodborne fungus of great public health importance. As determined by the molecular docking interactions of the library compounds indicated, the best interactions were found to occur between the nucleoside-diphosphate kinase protein 6XP7 and the test molecules Naringin (−6.771 kcal/mol), followed by Epigallocatechin gallate (−5.687 kcal/mol). Therefore, Naringin was opted for further validation with molecular dynamic simulations. The ligand–protein complex RMSD indicated a fairly stable Naringin-NDK ligand–protein complex throughout the simulation period (2–16 Å). In ADME and gastrointestinal absorbability testing, Naringin was observed to be orally bioavailable, with very low intestinal absorption and a bioavailability score of 0.17. This was further supported by the boiled egg analysis data, which clearly indicated that the GI absorption of the Naringin molecule was obscure. We found that naringin could be harmful only when swallowed at a median lethal dose between 2000 and 5000 mg/kg. In accordance with these findings, the toxicity prediction reports suggested that Naringin, found especially in citrus fruits and tomatoes, is safe for human consumption after further investigation. Overall, Naringin may be an ideal candidate for developing anti-A. fumigatus treatments and food packaging materials. Thus, this study addresses the simultaneous problems of discarded coffee waste management and antifungal resistance to available medications.