Molecular Modeling Approach Research Articles

Bioactive compounds from Morchella esculenta as potential inhibitors of RNA-binding protein La in ovarian cancer: a molecular modeling and quantum mechanics approach.

La protein is significantly expressed in various malignant tumors, including ovarian cancer (OC), which is related to the poor response to platinum-based chemotherapy. Thus, inhibiting La protein could control the expression of the potential downstream genes involved in promoting proliferation and chemotherapy resistance to OC, which could serve as a therapeutic intervention. Through a molecular docking approach, 12 compounds from Morchella esculenta were screened against the crystal structure of La protein and four hit compounds were identified, including beta-carotene, p-hydroxybenzoic acid, gamma-tocopherol, and alpha-tocopherol, with a binding affinity of - 10.7, - 8.1, - 7.9, and - 7.6kcal/mol, respectively, higher than pyridine-2-carboxylate (control), with a binding affinity of - 5.2kcal/mol. To explore the interaction of the hit compounds with the target receptor, they were selected for a molecular dynamic simulation and post-simulation analysis for 100ns. The result showed promising reliability of the ligands due to a stable interaction with the La protein crystal structure. Furthermore, the drug-likeness and physicochemical chemical properties of the compounds were investigated using ADMET study and density functional theory analysis, respectively, and the result shows that the hit compounds could serve as a promising starting for the development of novel LA protein inhibitors for OC therapeutics. Finally, this study compared HOMO and LUMO values from global hybrids with long-range corrected DFAs, and the result from the two followed the same qualitative pattern while calculating HOMO values; however, MO62X/cc-pVTZ could better predict LUMO values when considering a global hybrid.

Design and synthesis of chromene-1,2,3-triazole benzene sulfonamide hybrids as potent carbonic anhydrase-IX inhibitors against prostate cancer.

Considering the promising effects of molecular hybridization on drug discovery in recent years and the ongoing endeavors to develop bioactive scaffolds tethering the 1,2,3-triazole core, the present study sought to investigate whether the 1,2,3-triazole-linked chromene and benzene sulfonamide nucleus could exhibit activity against the human breast cancer cell line MCF-7 and prostate cancer cell line PC-3. To this end, three focused bioactive series of mono- and -bis-1,2,3-triazoles were effectively synthesized via copper-assisted cycloaddition of mono- and/or di-alkyne chromenone derivatives 2a and b and 9 with several sulfa drug azides 4a-d and 6. The resulting molecular derivatives were tested for cytotoxicity against prostate and breast cancer cells. Among the derivatives, 10a, 10c, and 10e exhibited potent cytotoxicity against PC-3 cells with IC50 values of 2.08, 7.57, and 5.52 μM compared to doxorubicin (IC50 = 2.31 μM) with potent inhibition of CA IX with IC50 values of 0.113, 0.134, and 0.214 μM. The most active compound, 10a, was tested for apoptosis-induction; it induced apoptosis by 31.9-fold cell cycle arrest at the G1-phase. Further, the molecular modeling approach highlighted the relevant binding affinity for the top-active compound 10a against CA IX as one of the most prominent PC-3 prostate cancer-associated biotargets.

Widespread circulation and transmission risk of Mycobacterium avium subsp. paratuberculosis at the livestock-wildlife-environment interface in a Mediterranean agro-forestry farmstead

Mycobacterium avium subsp. paratuberculosis (MAP) is the etiological agent of paratuberculosis, a chronic infection affecting ruminants and other species worldwide. Information on the ecological factors that increase infection risk at the livestock-wildlife-environment interface remains scarce. Thus, this work aimed at determining which factors modulate the exposure of a mammal community within a Mediterranean agro-forestry farmstead to MAP. Through field, molecular and ecological modeling approaches, MAP prevalence, distribution and spatial risk at the livestock-wildlife-environment was estimated in the study area by screening 436 samples (cattle, n = 150; wildlife, n = 206; soil, n = 80). Using molecular detection of IS900 as proxy, MAP was identified in ten wild mammal species. Being a central prey of mesocarnivores in Portugal, the high prevalence of MAP in the wild rabbit (19%) may be related with red fox's (22%). MAP was also detected in cattle managed in the farmstead (animal and herd prevalence, 54% and 100%) and in soil (44%), which may perpetuate intraspecies and interspecies transmission. Wildlife diversity showed a positive influence on MAP presence in wild mammals, while wildlife abundance showed a negative effect. Land use variables exerted distinct degrees of impact upon MAP detection in specific groups of mammals: mixed forest cover showed positive influence on carnivores, and shrubland showed positive effect on wild rabbits. The prevalence of MAP in cattle showed a negative influence on the detection of MAP in lagomorph, which may stem from wild rabbit lower density and avoidance of cattle areas. Based on explanatory variables, the spatial prediction of MAP occurrence in wildlife indicated two hotspots with increased exposure risk but future studies are needed to confirm this projection.This work represents the most comprehensive molecular survey of MAP occurrence and determinants in Mediterranean agroecosystems leveraging the principles and tools of community ecology, debating potential biological and ecological effects underlying MAP transmission.

Identification of novel inhibitors against VP40 protein of Marburg virus by integrating molecular modeling and dynamics approaches

Marburg virus (MV) is a highly etiological agent of haemorrhagic fever in humans and has spread across the world. Its outbreaks caused a 23–90% human death rate. However, there are currently no authorized preventive or curative measures yet. VP40 is the MV matrix protein, which builds protein shell underneath the viral envelope and confers hallmark filamentous. VP40 alone is able to induce assembly and budding of filamentous virus-like particles (VLPs), which resemble authentic virions. As a result, this research is credited with clarifying the function of VP40 and leading to the discovery of new therapeutic targets effective in combating MV disease (MVD). Virtual screening, molecular docking and molecular dynamics (MD) simulation were used to find the putative active chemicals based on a 3D pharmacophore model of the protein’s active site cavity. Initially, andrographidine-C, a potent inhibitor was selected for the development of the pharmacophore model. Later, a library of 30,000 compounds along with the andrographidine-C was docked against VP40 protein. Three best hits including avanafil, diuvaretin and macrourone were subjected to further MD simulation analysis, as these compounds had better binding affinities as compared to andrographidine-C. Furthermore, throughout the 100 ns simulations, the back bone of VP40 protein in presence of avanafil, diuvaretin and macrourone remained stable which was further validated by MM-PBSA analysis. Additionally, all of these compounds depict maximum drug-like properties. The predicted drugs based on the ligand, avanafil, diuvaretin and macrourone could be exploited and developed as an alternative or complementary therapy for the treatment of MVD. Communicated by Ramaswamy H. Sarma

A combined ligand-based and structure-based in silico molecular modeling approach to pinpoint the key structural attributes of hydroxamate derivatives as promising meprin β inhibitors

Human meprin β is a Zn2+-containing multidomain metalloprotease enzyme that belongs to the astacin family of the metzincin endopeptidase superfamily. Meprin β, with its diverse tissue expression pattern and wide substrate specificity, plays a significant role in various biological processes, including regulation of IL-6R pathways, lung fibrosis, collagen deposition, cellular migration, neurotoxic amyloid β levels, and inflammation. Again, meprin β is involved in Alzheimer’s disease, hyperkeratosis, glomerulonephritis, diabetic kidney injury, inflammatory bowel disease, and cancer. Despite a crucial role in diverse disease processes, no such promising inhibitors of meprin β are marketed to date. Thus, it is an unmet requirement to find novel promising meprin β inhibitors that hold promise as potential therapeutics. In this study, a series of arylsulfonamide and tertiary amine-based hydroxamate derivatives as meprin β inhibitors has been analyzed through ligand-based and structure-based in silico approaches to pinpoint their structural and physiochemical requirements crucial for exerting higher inhibitory potential. This study identified different crucial structural features such as arylcarboxylic acid, sulfonamide, and arylsulfonamide moieties, as well as hydrogen bond donor and hydrophobicity, inevitable for exerting higher meprin β inhibition, providing valuable insight for their further future development. Communicated by Ramaswamy H. Sarma

Molecular Dynamics Simulations for Surfactant Research (A Review)

This review discusses the theoretical basis and examples of implementation of various molecular modeling approaches to the investigation of the properties of surfactants. These surfactant properties include the ability to reduce the interfacial tension and alter the wettability and viscosity of solutions for the purposes of chemical flooding of crude oil reservoirs. A comparative analysis of the advantages and disadvantages of the existing molecular dynamics simulation methods is further provided. It is shown that molecular modeling methods can significantly facilitate the choice of surfactants for specific oil field conditions and can serve as a potential alternative to experimental measurements.

Carbenes trapping on Aluminum-Magnesium surface implanted with Silicon, Germanium, Tin: Promising of semiconductors by molecular modeling approach

Al-Mg surface doped silicon, germanium and tin is theoretically studied using first-principles density functional theory (DFT) at the CAM-B3LYP/EPR-III, LANL2DZ,6-31+G(d,p) level of theory to explore the chemical adsorption and corrosion inhibition of organic carbenes through coating process. The fluctuation of NQR is estimated the inhibiting role of pyridine and its derivatives (picoline, 3-picoline,4-picoline,2,4-lutidine) for (Si, Ge, Sn)-doped Al-Mg alloy nanosheet due to concerning nitrogen in the benzene ring of related heterocyclic compounds becoming close to the monolayer nanosurface of Al-Mg-X (X = Si, Ge, Sn) nanoalloys. The NMR spectroscopy remarks that (Si, Ge, Sn)-doped Al-Mg alloy nanosheet has maximum band wavelengths approximately between 10 ppm–2000 ppm accompanying the sharpest peaks for inhibitors → Al-Mg-X which are between 10 ppm–100 ppm. IR spectroscopy has exhibited that (Si, Ge, Sn)-doped Al-Mg alloy nanosheet with the fluctuation in the frequency of intra-atomic interaction leads us to the most influence in the vicinage atoms generated due to inter-atomic interaction. The maximum IR spectrum for complexes of [inhibitor → Al-Mg-X (X = Si, Ge, Sn)] is observed in the frequency range between 500 cm−1–3500 cm−1. This work exhibits that proper monitoring of the coating mechanism by Langmuir adsorption can illustrate inhibiting the aluminum nanoalloys corrosion through an investigation of their structural and thermodynamic properties. This work investigates the characteristics, band structure, and projected density of state (PDOS) of Al-Mg nanoalloy doped with Si, Ge, Sn elements for increasing the corrosion inhibition of the surface through adsorption of organic molecules of carbenes in the surface coatings process. This article can be helpful in a range of applications which uses Al-Mg alloy for the study of energy storage and adsorption of air pollution or water contamination. Many different approaches such as surface coatings, alloying and doping can be adopted to protect the surface.

An integrated network pharmacology and molecular modelling study of phytoconstituents targeting Alzheimer's disease

The present study involves the use of combined network pharmacology and molecular modelling approach for identifying important phytoconstituents that could modulate the functions of multiple therapeutic targets in Alzheimer’s disease. A list of botanicals reported in the literature for their efficacy in Alzheimer’s disease, the phytochemicals present in the botanicals were identified with the help of network pharmacology approach. The pharmacokinetic properties like blood brain barrier penetration and Lipinski’s rule of five for the selected phytoconstituents were analyzed. The major targets involved in the pathogenesis of Alzheimer’s disease were collected from the DisGeNET database. The selected proteins were subjected to topological analysis using Cytoscape software to identify the important targets in the network. The top 7 phytoconstituents and 5 proteins were subjected to molecular docking, MM-GBSA and molecular dynamics studies. A total of 15 plants and 1443 phytoconstituents were identified through a literature survey and from several databases. The pharmacokinetics study revealed that 7 phytoconstituents - glycyrrhisoflavone, eugenol, ferulic acid, methyl jasmonate, geranyl formate, formononetin, and elemicin- exhibited favourable pharmacokinetic properties. Five targets, HMOX1, CNR1, STAT3, HDAC2, and MAOB were found to be important in the network of 3300 proteins based on degree centrality and betweenness centrality. Among the seven phytoconstituents, glycyrrhisoflavone exhibited good dock scores and free energy value. Based on this, the stability of glycyrrhisoflavone with the five selected targets were analyzed using molecular dynamics study. Glycyrrhisoflavone showed good stability with most of the selected therapeutic targets. The current study reveals that the selected phytoconstituents i.e glycyrrhisoflavone, eugenol, ferulic acid, methyl jasmonate, geranyl formate, formononetin, and elemicin could serve as good lead molecules in treatment and management of Alzheimer’s disease through modulation of multiple targets.

Inhibition potential of natural flavonoids against selected omicron (B.1.19) mutations in the spike receptor binding domain of SARS-CoV-2: a molecular modeling approach

The omicron (B.1.19) variant of contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered a variant of concern (VOC) due to its increased transmissibility and highly infectious nature. The spike receptor-binding domain (RBD) is a hotspot of mutations and is regarded as a prominent target for screening drug candidates owing to its crucial role in viral entry and immune evasion. To date, no effective therapy or antivirals have been reported; therefore, there is an urgent need for rapid screening of antivirals. An extensive molecular modelling study has been performed with the primary goal to assess the inhibition potential of natural flavonoids as inhibitors against RBD from a manually curated library. Out of 40 natural flavonoids, five natural flavonoids, namely tomentin A (−8.7 kcal/mol), tomentin C (−8.6 kcal/mol), hyperoside (−8.4 kcal/mol), catechin gallate (−8.3 kcal/mol), and corylifol A (−8.2 kcal/mol), have been considered as the top-ranked compounds based on their binding affinity and molecular interaction profiling. The state-of-the-art molecular dynamics (MD) simulations of these top-ranked compounds in complex with RBD exhibited stable dynamics and structural compactness patterns on 200 nanoseconds. Additionally, complexes of these molecules demonstrated favorable free binding energies and affirmed the docking and simulation results. Moreover, the post-simulation validation of these interacted flavonoids using principal component analysis (PCA) revealed stable interaction patterns with RBD. The integrated results suggest that tomentin A, tomentin C, hyperoside, catechin gallate, and corylifol A might be effective against the emerging variants of SARS-CoV-2 and should be further evaluated using in-vitro and in-vivo experiments. Communicated by Ramaswamy H. Sarma

Design of alkyl-substituted aminothiazoles to optimise corrosion inhibition for galvanised steel: A combined experimental and molecular modelling approach

This work proposes a combined experimental and molecular modelling approach to clarify the complex substitution effect of aminothiazole as corrosion inhibitor for galvanised steel in saline aqueous environments. Electrochemical results have shown that introducing alkyl residues ameliorates inhibition efficiency to varied degrees. Umbrella sampling simulations supplemented by a newly developed GFN-force-field-based molecular approach reveal that the particular adsorption state renders a hydrophobic environment at the outer surface, where increased alkyl size leads to greater hydrophobicity for corrosion inhibition. Such an effect becomes less prominent with increasing concentration, attributed to the enhanced intermolecular interaction destabilising the adsorption process.

Molecular modelling of energy storage performance on metal organic frameworks/ethane nanoparticles nanofluids mixtures and derivatives

Through the utilization of optimum working fluids, thermodynamic cycles may perform more effectively. In this study, we used molecular modeling approaches to conduct computational studies on nanofluids of ethane and its derivatives with metal organic frameworks (ZIF-8). DMol3 was used to investigate the structure and electrical behavior of nanomaterials prior to as well as following fluid adsorption. The adsorption behavior of the refrigerant gases ethane (R-170), fluroethane (R-161), and difluroethane (R-152a) on ZIF-8 was investigated using grand canonical Monte Carlo simulations at various temperatures. Additionally, R-170/ZIF-8, R-161/ZIF-8, and R-152a/ZIF-8 nanofluids' stability and thermal energy storage traits were assessed. The outcomes demonstrate a decrease in the order of R-170 > R-152a > R-161 in the adsorption of the fluids on ZIF-8. Additionally, adding ZIF-8 nanomaterial to R-170, R-161 and R-152a fluids improved their ability to store energy, but improvements at higher ZIF-8 concentrations revealed sensitive dependence on the pressure and temperature conditions, particularly the fluid under consideration's critical temperature. To validate the computational findings, they were contrasted with previously collected experimental data.

Characterising ATP binding activity of PilB ATPase of Shewanella oneidensis MR-1 using a molecular modeling and simulations approach

Characterising ATP binding activity of PilB ATPase of Shewanella oneidensis MR-1 using a molecular modeling and simulations approach

Optimal molecular binding data and pharmacokinetic profiles of novel potential triple-action inhibitors of chymase, spleen tyrosine kinase, and prostaglandin D2 receptor in the treatment of asthma

BackgroundAsthma is a chronic and complex pulmonary condition that affects the airways. A total of 250,000 asthma-related deaths are recorded annually and several proteins including chymase, spleen tyrosine kinase, and prostaglandin D2 receptor have been implicated in the pathophysiology of asthma. Different anti-inflammatory drugs have been developed for the treatment of asthma, particularly corticosteroids, but the associated adverse reactions cannot be overlooked. It is therefore of interest to identify and develop small molecule inhibitors of the integral proteins associated with asthma that have very little or no side effects. Herein, a molecular modeling approach was employed to screen the bioactive compounds in Chromolaena odorata and identify compounds with high binding affinity to the protein targets. ResultsFive compounds were identified after rigorous and precise molecular screening namely (−)-epicatechin, chlorogenic acid, ombuine, quercetagetin, and quercetin 3-O-rutinoside. These compounds generally showed impressive binding to all the targets understudy. However, chlorogenic acid, quercetagetin, and quercetin 3-O-rutinoside showed better prospects in terms of triple-action inhibition. Further pulmonary and oral pharmacokinetics showed positive results for all the reported compounds. The generated pharmacophore model showed hydrogen bond donor, hydrogen bond acceptor, and aromatic rings as basic structural features required for triple action inhibition. ConclusionThese findings suggest that these compounds could be explored as triple-action inhibitors of the protein targets. They are, therefore, recommended for further analysis.

Napthyridine-derived compounds as promising inhibitors for Staphylococcus aureus CrtM: a primer for the discovery of potential anti-Staphylococcus aureus agents.

The disease-free existence of humans is constantly under attack by a variety of infections caused by a variety of organisms including bacteria. Notable among the bacteria is Staphylococcus aureus which is an etiological organism for infections including impetigo, folliculitis, and furuncles. The response of the human immune system against this disease is often neutralized by the production of a pigment called Staphyloxanthin (STX) via a series of reactions mediated by several enzymes. Among these enzymes, dehydrosqualene synthase, also known as CrtM, has emerged as a viable drug target due to its role in mediating the first step of the pathway. Consequently, this study employs molecular modeling approaches including molecular docking, quantum mechanical calculations, and molecular dynamics (MD) simulations among others to investigate the potential of napthyridine derivatives to serve as inhibitors of the CrtM. The results of the study revealed the high binding affinities of the compounds for the target as demonstrated by their docking scores, while further subjection to screening pipeline aimed at determining their fitness for development into drugs revealed just one compound namely 6-[[1-[(2-fluorophenyl) methyl]triazol-4-yl]methoxy]-4-oxo-1H-1,5-naphthyridine-3-carboxylic acid as the compound with good drug-like, pharmacokinetics, and toxicity properties profiles. A 100 ns-long MD simulation of the complexes formed after molecular docking revealed the stable interaction of the compound with the target. Ultimately, this study can be a promising outlet to discover a weapon to fight against clinically resistant bacteria, however, further experimental studies are suggested to carry out in the wet lab, pre-clinical, and clinical levels.

Integrated virtual screening, molecular modeling and machine learning approaches revealed potential natural inhibitors for epilepsy

Epilepsy, a prevalent chronic disorder of the central nervous system, is typified by recurrent seizures. Present treatments predominantly offer symptomatic relief by managing seizures, yet fall short of influencing epileptogenesis. This study endeavored to identify novel phytochemicals with potential therapeutic efficacy against S100B, an influential protein in epileptogenesis, through an innovative application of machine learning-enabled virtual screening. Our study incorporated the use of multiple machine learning algorithms, including Support Vector Machine (SVM), k-Nearest Neighbors (kNN), Naive Bayes (NB), and Random Forest (RF). These algorithms were employed not only for virtual screening but also for essential feature extraction and selection, enhancing our ability to distinguish between active and inactive compounds. Among the tested machine learning algorithms, the RF model outshone the rest, delivering an impressive 93.43 % accuracy on both training and test datasets. This robust RF model was leveraged to sift through the library of 9,000 phytochemicals, culminating in the identification of 180 potential inhibitors of S100B. These 180 active compounds were than docked with the active site of S100B proteins. The results of our study highlighted that the 6-(3,12-dihydroxy-4,10,13-trimethyl-7,11-dioxo-2,3,4,5,6,12,14,15,16,17-decahydro-1H cyclopenta[a] phenanthren −17-yl)-2-methyl-3-methylideneheptanoic acid, rhinacanthin K, thiobinupharidine, scopadulcic acid, and maslinic acid form significant interactions within the binding pocket of S100B, resulting in stable complexes. This underscores their potential role as S100B antagonists, thereby presenting novel therapeutic possibilities for epilepsy management. To sum up, this study's deployment of machine learning in conjunction with virtual screening not only has the potential to unearth new epilepsy therapeutics but also underscores the transformative potential of these advanced computational techniques in streamlining and enhancing drug discovery processes.

In Vitro Characterization of the Interactions of Human Serum Albumin with Rosuvastatin and Atorvastatin Using Fluorescence Spectroscopy and Molecular Modeling

Human serum albumin (HSA) is one of the most important transporters for drugs in the systemic circulation. In this study, we investigated the interaction of rosuvastatin (ROS) and atorvastatin (ATO) with HSA. Binding of a drug molecule to HSA significantly affects the pharmacokinetics of the drug as it increases drug solubility in plasma, decreases toxicity and protects molecules from oxidation. This study was made using fluorescence spectroscopy and molecular modeling approach. Fluorescence spectra were recorded for two different statins brands at seven different concentrations. The results revealed that both statins (ROS and ATO) cause the fluorescence quenching of the HSA solution. ROS and ATO binds strongly to HSA with the binding constant (Kb) of 1.0246×106 and 0,9018×106, respectively. In addition, it was observed that high concentrations of ATO cause a shift of the emission maximum towards longer wavelengths (red-shift), which may be due to the unfolding of protein chains or denaturation. Furthermore, it was calculated that HSA possesses one binding site for ROS and ATO. Results from molecular docking showed that ROS has a higher affinity for Sudlow site I compared to Sudlow site II and the main binding forces are hydrogen bonds. ATO has nearly equal affinity for both binding sites on HSA, and the main binding forces are hydrophobic interactions.

Integrated molecular modeling and dynamics approaches revealed the mechanism of selective inhibition of HDAC6/8

The high structural homology of histone deacetylases 6 and 8 (HDAC6/8) poses a challenge in achieving isoform selectivity and has resulted in adverse side effects due to pan-inhibition in clinical applications. Additionally, the rational design of dual-target inhibitors, centered on HDAC6/8, demands a profound understanding of their selectivity mechanisms. Addressing the urgent need for enhanced specificity in the development of inhibitors targeting specific isoforms, we elucidate the mechanism underpinning the selective inhibition of HDAC6/8 inhibitors through in-silico strategies. The hydrogen bonding interaction with Asp101 and Tyr306 is a key factor that enables compound 12b to selectively inhibit HDAC8. Its favorable spatial orientation places the Cap group of 12b between Tyr306 and Tyr100, resulting in an overall L-shaped conformation. These two factors significantly contribute to the selective inhibitory activity of 12b against HDAC8. The zinc binding group (ZBG) of compound NN-390 forms a hydrogen bond with His610, a key residue of HDAC6, facilitating stable chelation with zinc ions. In addition, the Cap group of NN-390 interacts with Phe620 and Phe680 via van der Waals forces, leading to an overall Y-shaped conformation. The aforementioned factors are the main reasons for the selective inhibition of HDAC6 by NN-390. Furthermore, whether the Cap group is in the para or meta-position will influence the selective inhibition of either HDAC6 or HDAC8. We believe these clues can offer valuable insights for the rational design of selective inhibitors targeting HDAC6/8 and pave the way for rational design of dual-target HDAC6/8-based inhibitors. Communicated by Ramaswamy H. Sarma

Interaction between the antioxidant compound safranal and α-chymotrypsin in spectroscopic fields and molecular modeling approaches

Among various herbal plants, saffron has been the subject of study in various medical and food fields. Among the compounds of saffron, safranal is one of them. Safranal is a monoterpene aldehyde. The precursor of safranal is called picrocrocin, whose hydrolysis leads to the production of safranal. picrocrocin has two sugar components and aglycone. sugar component was separated during the drying process of saffron and safranal is produced. Saffron is the cause of the saffron aroma. Previous studies have shown that safranal offers many benefits such as antioxidants, blood pressure regulation and anti-tumor qualities. On the other hand, α-Chy is an enzyme secreted by the pancreas into the intestine and then acts as an efficient protease. In this study, various methods, such as molecular dynamics (MD) simulation and molecular binding, and different spectroscopic techniques, as well as protein stability techniques, were used to investigate the possible interactions between safranal and α-Chy. UV spectroscopic studies were showing that the existence of safranal decreased α-Chy absorption intensity. safranal caused the intrinsic fluorescence of α-Chy to be quenched too. According to the Stern-Volmer equation, the interaction between safranal and α-Chy was of the static type. In thermodynamic calculations, the interaction between safranal and α-Chy was stabilized by hydrophobic forces. And it was found that this interaction continued spontaneously. These results were, thus, consistent with the Docking data simulation (with the negative ΔG° number and positive changes in enthalpy and entropy). The thermal stability of α-Chy was also measured, showing that its melting point was shifted to a higher threshold as a result of the interaction. also, MD simulation indicated that α-Chy became more stable in the presence of safranal. In this paper, all the results of the laboratory techniques were confirmed by molecular dynamic simulations, so the correctness of the results was confirmed. From this research, we hope to carefully observe the possible changes in the behavior and structure of the enzyme in the presence of safranal. Communicated by Ramaswamy H. Sarma

Photodegradation of Triclosan on the Kaolinite Surface: Kinetic, Mechanistic, and Molecular Modeling Approach.

The photodegradation of triclosan (TCS) was investigated on the kaolinite surface. The quantum yield was evaluated, and the photoproducts were identified by HPLC/MS (LC/Q-TOF), showing that the phototransformation is completely different from that reported in aqueous solutions. In particular, the formation of dioxin derivatives was fostered and occurred with a higher efficiency when compared to aqueous solutions. This suggests that TCS has specific interactions with the clay that clearly modifies its photochemical behavior. Moreover, it has also been shown that higher concentrations of TCS, namely, higher than 1.0 μmol g-1 of kaolinite, lead to a significant decrease of the photodegradation rate constant and enhance the formation yield of dimer-type photoproducts. This suggests that the distribution of TCS is clearly not homogeneous at the clay surface and the formation of aggregates is more likely occurring. To get a better insight into this specific interaction, a molecular dynamic modeling of TCS adsorption at the surface of kaolinite was carried out. This clearly shows that when equilibrium is reached, TCS binds to the kaolinite surface by hydrogen bonds involving the phenol function of TCS and the hydroxyl groups of the kaolinite surface. Such behavior confers a particular conformation to the adsorbed TCS that is different from that obtained in water and which could be a key step to partially explain the specific photochemical reactivity in both media. In addition, several TCS molecules appear to interact with each other through the π-stacking (aromatic stacking) process while retaining this hydrogen bond with the kaolinite surface. This is clearly in favor of cluster formation on the clay surface and promotes dimer-type photoproducts.

Design and characterization of a multi-epitope vaccine against Clostridium botulinum A3 Loch Maree intoxication in humans

Clostridium botulinum Loch Maree expresses an extremely potent botulinum neurotoxin subtype, A3 causing botulism and several gastrointestinal disorders in mammals. Several recombinant vaccines have been developed for human botulism and no vaccine is currently available for the treatment of diseases caused by other virulence factors. Hence, we designed, constructed, and characterized a multi-epitope vaccine from new virulence proteins identified from this organism using an immunoinformatics approach. The vaccine construct used in this study was designed from 6B cell linear epitopes, 12 cytotoxic T cell lymphocyte epitopes, and 15 helper T cell lymphocyte epitopes, with a defensin adjuvant and adjusting linker sequences. A molecular modeling approach was used to model, refine, and validate the 3D structure of the vaccine construct. Molecular docking studies were performed to determine the stability of the molecular interactions between the vaccine construct and human toll-like receptor 7. The in silico molecular cloning was used to clone a codon-optimized synthetic vaccine gene in pCYB1 vector and expressed in Escherichia coli. The results of this study identified six new virulence proteins: peptidoglycan hydrolase, SCP-like extracellular protein, N-acetylmuramoyl-l-alanine amidase, putative membrane protein, drug/metabolite exporter, and bacillolysin. The top B-cell, cytotoxic T-cell lymphocyte, and helper T-lymphocyte epitopes were predicted from these virulence proteins with greater accuracy and reliability. HLA-A*02:01 and HLA-A*03:01 were identified as HLA-A-binding alleles for cytotoxic T-cell lymphocyte epitopes. DRB1*0110 and DRB1*0115 are the dominant alleles that bind to helper T-cell lymphocyte epitopes. The synthetic gene construct was highly expressed in a heterologous host and produced considerable amounts of antigenic protein. The multi-epitope vaccine is more conservative in the sequence-structure–function link, immunogenic with less allergenicity, and possibly provokes cellular and humoral immunity. The present study suggests that the designed multi-epitope vaccine is a promising prophylactic candidate for the virulence and intoxication caused by subtype A3 strains.