Computational Docking Simulations Research Articles

How could the physical properties of poly(vinyl alcohol) influence enzymatic activity? A Detailed Study on Nanofibrous Catalysts Incorporating a Lipase from Burkholderia cepacia

Utilizing the electrospinning technique to entrap enzymes within nanofibers (providing nanofibrous enzyme catalysts, NEC) offers promising avenues for scientific and industrial sector as well. While numerous instances of poly(vinyl alcohol) (PVA)‐based nanofibrous biocatalysts have been documented, a comprehensive investigation to characterize the effect of PVA on catalytic activity is notably lacking. This study systematically investigates the effect of PVA properties, such as molecular weight (24‐205 kDa), degree of hydrolysis (DoH 88% and 98%), and polymer concentration (6‐16 wt%), on the structure of PVA nanofibers and on the biocatalytic properties of a lipase from Burkholderia cepacia (BcL) entrapped into PVA nanofibers ensuring 100% yield of immobilization. The PVA‐enzyme interactions were studied using viscometry, scanning electron microscopy, Raman mapping, differential scanning calorimetry and computational docking simulations. Stereoselective hydrolysis and transesterification was used to evaluate enzyme activity. Results showed that the molecular weight and DoH of PVA have a significant effect on the biocatalytic activity of nanofibrous enzyme catalysts. Remarkably, activity yields (mostly exceeded 100%, with maximal yields achieved using fully hydrolyzed PVA) with a molecular weight of 61 kDa providing a tenfold increase in the specific enzymatic activity of BcL immobilized in nanofibers (90.6 U×g−1) compared to its native form (9.0 U×g−1).

Elucidation of the Binding Interaction between β-sitosterol and Lysozyme using Molecular Docking, Molecular Dynamics and Surface Plasmon Resonance Analysis.

In this study, the binding behavior of β-sitosterol with lysozyme (LZM) was elucidated by surface plasmon resonance (SPR), computational molecular docking and molecular dynamics simulation studies. Chicken egg white lysozyme (CEWLZM) served as a model protein. Tri-N-acetylchitotriose (NAG3) was used in the redocking experiments to generate precise binding location of the protein. β-sitosterol displayed a slightly better binding energy (-6.68±0.04 kcal/mol) compared to NAG3. Further molecular dynamics simulations and MMPBSA analysis revealed that residues Glu35, Gln57-Asn59, Trp62, Ile98, Ala107 and Trp108 contribute to the binding energy. Then, 2.5 mg/mL CEWLZM, 1X PBS buffer (pH 7.4) as running and coupling buffers, 30 μL/min as flow rate were applied for SPR analysis. Serial β-sitosterol injections (20-150 μM) were performed through SPR sensor surface. According to SPR binding study, KD value for β-sitosterol-CEWLZM binding interaction was calculated as 71.34±9.79 μM. The results could provide essential knowledge for nutrition, pharmaceutical science, and oral biology.

Modulation of the LIMK Pathway by Myricetin: A Protective Strategy Against Neurological Impairments in Spinal Cord Injury.

Spinal cord injury (SCI), one of the major disabilities concerning central nervous system injury, results in permanent tissue loss and neurological impairment. The existing therapeutic options for SCI are limited and predominantly consist of chemical compounds. In this study, we delved into the neuroprotective effects of myricetin, a natural flavonoid compound, and the underlying mechanisms, specifically in the context of SCI, utilizing an in vivo model. Previously, our investigations revealed an elevation in the phosphorylated form of Lin-11, Isl-1, and Mec-3 kinase1 (LIMK1) at chronic time points postinjury, coinciding with neuronal loss and scar formation. Our primary objective here was to assess the potential neuroprotective properties of myricetin in SCI and to ascertain if these effects were linked to LIMK inhibition, a hitherto unexamined pathway to date. Computational docking and molecular dynamics simulation studies were performed to assess myricetin's potential to bind with LIMK. Then, using a rat contusion model, SCI was induced and different molecular techniques (Western blot, Evans Blue assay, quantitative reverse transcription polymerase chain reaction and immunohistochemistry) were performed to determine the effects of myricetin. Remarkably, computational docking models identified myricetin as having a better interaction profile with LIMK than standard. Subsequent to myricetin treatment, a significant downregulation in phosphorylated LIMK expression was observed at chronic time points. This reduction correlated with a notable decrease in glial and fibrotic scar formation, and enhanced neuroprotection indicating a positive outcome in vivo. In summary, our findings underscore myricetin's potential as a bioactive compound capable of attenuating SCI-induced injury cascades by targeting the LIMK pathway.

Flavonoids as Pyruvate Kinase M2 Inhibitor: An In silico Analysis

Background: The prevalence of cancer in developing nations is a significant issue of concern. As a result of diverse global influences, this condition has surpassed coronary ailments to become the foremost cause of mortality. The role of PKM2 (Muscle Pyruvate Kinase 2) has garnered significant interest in the quest for agents in cancer progression. Flavonoids exhibit promise as a framework for the advancement of chemotherapeutic agents targeting cancer. Objective: The principal aim of the present in silico investigation was to ascertain flavonoids as potential anticancer agents capable of inhibiting the PKM2 enzyme. Methods: The preferred ligand molecules were docked to the human PKM2 enzyme using a computational molecular docking simulation technique to determine their affinity for the same enzyme. The molecular docking simulation was carried out using the AutoDock Vina software. Results: The chosen flavonoid docked well with the PKM2 enzyme, suggesting it may stimulate autophagy, hence acting as an anticancer agent. Conclusion: In in silico studies, the chosen flavonoids showed a strong binding affinity, indicating that all of them impede the human PKM2 enzyme and have the potential to be used as cancer treatment alternatives.

Covalent assembly-based two-photon fluorescent probes for in situ visualizing nitroreductase activities: From cancer cells to human cancer tissues

Nitroreductase (NTR) is widely regarded as a biomarker whose enzymatic activity correlates with the degree of hypoxia in solid malignant tumors. Herein, we utilized 2-dimethylamino-7-hydroxynaphthalene as fluorophore linked diverse nitroaromatic groups to obtain four NTR-activatable two-photon fluorescent probes based on covalent assembly strategy. With the help of computer docking simulation and in vitro assay, the sulfonate-based probe XN3 was proved to be able to identify NTR activity with best performances in rapid response, outstanding specificity, and sensitivity in comparison with the other three probes. Furthermore, XN3 could detect the degree of hypoxia by monitoring NTR activity in kinds of cancer cells with remarkable signal-to-noise ratios. In cancer tissue sections of the breast and liver in mice, XN3 had the ability to differentiate between healthy and tumorous tissues, and possessed excellent fluorescence stability, high tissue penetration and low tissue autofluorescence. Finally, XN3 was successfully utilized for in situ visualizing NTR activities in human transverse colon and rectal cancer tissues, respectively. The findings suggested that XN3 could directly identify the boundary between cancer and normal tissues by monitoring NTR activities, which provides a new method for imaging diagnosis and intraoperative navigation of tumor tissue.

Synthesis and characterisation of dipyrromethene Cu(II) complexes: A preliminary DNA intercalation study

Copper complexes of the bilirubin bile pigment have been shown to affect DNA. It was suggested that the copper ions within these metal-bilirubin therapeutics bind to bilirubin through the two dipyrromethene moieties, thus highlighting the potential therapeutic impact of these dipyrromethene moieties. Here, we report the synthesis and characterization of two bilirubin biomimetic copper complexes, CuL1 and CuL2, featuring tetrahedral dipyrromethene moieties. DNA binding studies reveal significant affinities for both complexes, with CuL1 displaying a log Ka of 4.70 ± 0.02, with a corresponding Gibbs free energy change (ΔG) of –26.8 kJ/mol at 25 °C, indicating a moderate-to-high DNA affinity. CuL2 showed a slightly higher affinity with log Ka of 4.88 ± 0.02, with a corresponding ΔG of –27.4 kJ/mol at 25 °C. These experimental findings aligned closely with computational docking G-scores, which yielded –32.9 kJ/mol for CuL1 and –34.8 kJ/mol for CuL2, respectively. Viscosity, gel electrophoresis, and absorption studies support an intercalative binding mechanism, which was further confirmed by computational docking and molecular dynamics simulations. These findings suggest that copper dipyrromethene complexes may exert therapeutic effects through DNA interaction, warranting further investigation involving in vitro cell cultures for drug development potential.

Antimalarial Delivery with a Ferritin-Based Protein Cage: A Step toward Developing Smart Therapeutics against Malaria.

Over the past two decades, the utilization of protein cages has witnessed exponential growth driven by their extensive applications in biotechnology and therapeutics. In the context of the recent Covid-19 pandemic, protein-cage-based scaffolds played a pivotal role in vaccine development. Beyond vaccines, these protein cages have proven valuable in diverse drug delivery applications thanks to their distinctive architecture and structural stability. Among the various types of protein cages, ferritin-based cages have taken the lead in drug delivery applications. This is primarily attributed to their ease of production, exceptional thermal stability, and nontoxic nature. While ferritin-based cages are commonly employed in anticancer drug delivery and contrast agent delivery, their efficacy in malarial drug delivery had not been explored until this study. In this investigation, several antimalarial drugs were encapsulated within horse spleen ferritin, and the binding and loading processes were validated through both experimental and computational techniques. The data unequivocally demonstrate the facile incorporation of antimalarial drugs into ferritin without disrupting its three-dimensional structure. Computational docking and molecular dynamics simulations were employed to pinpoint the precise location of the drug binding site within ferritin. Subsequent efficacy testing on Plasmodium revealed that the developed nanoconjugate, comprising the drug-ferritin conjugate, exhibited significant effectiveness in eradicating the parasite. In conclusion, the findings strongly indicate that ferritin-based carrier systems hold tremendous promise for the future of antimalarial drug delivery, offering high selectivity and limited side effects.

Hybrids of 4-aminosalicylic acid with dual anti-mycobacterial and anti-inflammatory activities: Synthesis, biological evaluation, in silico investigation and structure-activity relationships exploration

Studies point toward a beneficial effect of NSAIDs as an adjunctive tuberculosis treatment. To discover new antitubercular compounds with anti-inflammatory activity and favorable safety profiles, three new series of non-carboxylic 4-aminosalicylic acid hybrids bearing various hydrazides (3 and 5), heterocyclic scaffolds (6–15), hydrazones (16a–d) and carboxylic analogues bearing 1,2,3-triazoles (19 and 20), were synthesized. The synthesized hybrids were evaluated for their antimycobacterial activity against H37Rv using MABA assay. Among them, compounds 8, 16a–c, 19 and 20 exhibited MIC values (9.90–37.62 µM) with good selectivity index. 16b and 20 were the most potent with MIC 9.90 and 11.40 µM, respectively. Based on an in silico docking study at COX-2 active site, 11 compounds 13a, 13b, 14a–g, 16a and 16b were selected for testing their COX-2 inhibition. The most active compounds, 13a, 16a and 16b were further tested for COX-1 and 5-LOX inhibition. Also, their COX-2 selectivity indices (SI) were determined. 16a and 16b showed the highest potency and selectivity against COX-2 IC50 = 0.31, 1.26 µg/mL, respectively, and 5-LOX with IC50 = 5.49, 25.44 µg/mL, respectively. Computational docking simulations and in Silico ADME/pharmacokinetic studies for the most active hybrids were performed and discussed. Thus structure-activity relationships were explored. In conclusion, compounds 16a and 16b represent a good starting point for the development of new potential drugs of dual antitubercular and anti-inflammatory activities.

Novel derivatives of Costus igneus towards potentiality against diabetes mellitus receptors: ADME/Tox profiling, Computational Docking, and Molecular Dynamics Simulation study

Costus igneus has been practiced to alleviate a range of human ailments and the substantial vision was to explore potential bio-active compounds of Costus igneus to better comprehend the underlying mechanism in the management of diabetes. In-silico approach using AutoDock and Desmond, the anti-diabetic efficacy of discovered phytochemicals was evaluated. The best-docked were chosen for simulation studies. The molecular dynamic modelling showed that the complexes of ligands with receptors were stable during a time of 100 ns, which further confirmed and enhanced their significant binding affinity. According to docking scores and simulation studies, these phytocompounds could be targeted to garner efficient preventive medications for diabetes from a biological source using contemporary technology, and further in vivo and in vitro research of these compounds may be encouraged in the search for a potent treatment for the disease.

Identification of Interleukin (IL)-33 Inhibitory Constituents from Canavalia gladiata Pods.

Interleukin (IL)-33, a member of the IL-1 cytokine family, plays a vital role in immune system regulation and inflammation, with oxidative stress being implicated in its expression. During the search for compounds from natural sources with potential as therapeutic agents for allergic diseases via IL-33 signal modulation, we discovered significant IL-33 inhibitory activity in the methanol extract of Canavalia gladiata (sword bean) pods. Through chromatographic separation and liquid chromatography-mass spectrometry, we isolated 11 compounds (1-11) from the methanol extract. Furthermore, we assessed the inhibitory effects of these substances on IL-33/ST2 signaling in processes related to inflammatory and autoimmune diseases using an enzyme-linked immunosorbent assay. Among them, compounds 7, 10, and 11 exhibited substantial IL-33 inhibitory efficacy, with values reaching 78%, 86%, and 79% at 100 µM, respectively. Remarkably, compounds 7, 10, and 11 demonstrated significant and dose-dependent inhibition of IL-33 signaling at concentrations of 10, 50, and 100 µM. Computational molecular docking and dynamic simulations further elucidated the underlying mechanisms. These findings have promising pharmacological implications for allergy prevention and treatment associated with flavonoid glycosides derived from C. gladiata.

Structural basis for the inhibition of the HCoV-NL63 main protease Mpro by X77

Human coronaviruses are a group of pathogens that primarily cause respiratory and intestinal diseases. Infection can easily cause respiratory symptoms, as well as a variety of serious complications. There are several types of human coronaviruses, such as SARS-CoV, MERS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, and SARS-CoV-2. The prevalence of COVID-19 has led to a growing focus on drug research against human coronaviruses. The main protease (Mpro) from human coronaviruses is a relatively conserved that controls viral replication. X77 was discovered to have extremely high inhibitory activity against SARS-CoV-2 Mpro through the use of computer-simulated docking. In this paper, we have resolved the crystal structure of the HCoV-NL63 Mpro complexed with X77 and analyzed their interaction in detail. This data provides essential information for solving their binding modes and their structural determinants. Then, we compared the binding modes of X77 with SARS-CoV-2 Mpro and HCoV-NL63 Mpro in detail. This study illustrates the structural basis of HCoV-NL63 Mpro binding to the inhibitor X77. The structural insights derived from this study will inform the development of new drugs with broad-spectrum resistance to human coronaviruses.

Computational design, docking, and molecular dynamics simulation study of RNA helicase inhibitors of dengue virus.

RNA viruses are complex pathogens in terms of their genetic makeup, mutation frequency, and transmission modes. They contain the RNA helicase enzyme, which plays a crucial role in the viral genome replication process. This work aims to develop and screen a potential molecule that could function as a dengue virus (DENV) RNA helicase inhibitor. The present study was performed by taking 26 potential derivatives of gedunin phytochemicals from the PubChem database as ligands. The binding study of the compounds were analyzed by in silico docking method considering DENV RNA helicase enzyme as the receptor. After a thorough analysis of the docking scores, toxicity, and physicochemical properties, compound tetrahydrogedunin was obtained as the best. Based on tetrahydrogedunin molecular structure, 100 drug-like molecules were designed using the Data Warrior tool. After the screening process for drug-likeness and ADMET properties, the derivative number 42 was considered as the promising. Further comparative docking of derivative 42 and a standard inhibitor molecule ST-610 with DENV RNA helicase enzyme showed binding affinity as -10.0 kcal/mol and -9.6 kcal/mol, respectively. The favorable interaction between DENV RNA helicase and derivative 42 was further validated by 50 nanoseconds molecular dynamics simulation and MM-GBSA analysis. Since the antiviral activity of derivative 42 has not been reported till date, the compound was predicted as a novel therapeutic molecule that can act against the dengue virus (DENV) RNA helicase enzyme.

The Features of Shared Genes among Transcriptomes Probed in Atopic Dermatitis, Psoriasis, and Inflammatory Acne: S100A9 Selection as the Target Gene.

Atopic dermatitis (AD), psoriasis (PS), and inflammatory acne (IA) are well-known as inflammatory skin diseases. Studies of the transcriptome with altered expression levels have reported a large number of dysregulated genes and gene clusters, particularly those involved in inflammatory skin diseases. To identify genes commonly shared in AD, PS, and IA that are potential therapeutic targets, we have identified consistently dysregulated genes and disease modules that overlap with AD, PS, and IA. Microarray data from AD, PS, and IA patients were downloaded from Gene Expression Omnibus (GEO), and identification of differentially expressed genes from microarrays of AD, PS, and IA was conducted. Subsequently, gene ontology and gene set enrichment analysis, detection of disease modules with known disease-associated genes, construction of the protein-protein interaction (PPI) network, and PPI sub-mapping analysis of shared genes were performed. Finally, the computational docking simulations between the selected target gene and inhibitors were conducted. We identified 50 shared genes (36 up-regulated and 14 down-regulated) and disease modules for each disease. Among the shared genes, 20 common genes in PPI network were detected such as LCK, DLGAP5, SELL, CEP55, CDC20, RRM2, S100A7, S100A9, MCM10, AURKA, CCNB1, CHEK1, BTC, IL1F7, AGTR1, HABP4, SERPINB13, RPS6KA4, GZMB, and TRIP13. Finally, S100A9 was selected as the target gene for therapeutics. Docking simulations between S100A9 and known inhibitors indicated several key binding residues, and based on this result, we suggested several cannabinoids such as WIN-55212-2, JZL184, GP1a, Nabilone, Ajulemic acid, and JWH-122 could be potential candidates for a clinical study for AD, PS, and IA via inhibition of S100A9-related pathway. Overall, our approach may become an effective strategy for discovering new disease candidate genes for inflammatory skin diseases with a reevaluation of clinical data.

Computational Approaches Molecular Docking and MD Simulation Establishes the Potential COVID-19 Main Protease Inhibitors from Natural Products

Aim: COVID-19 was classified as a pandemic by the World Health Organization (WHO) on March 11, 2020. No reliable cure, however, was found. To prevent viral replication, complementary therapy with antiviral and antimalarial medications were used. However, due to their synthetic origin, they have a lot of side effects. To overcome this bane natural origin drugs were repositioned. Background: As repositioned drugs do not undergo a pro-long process of pre-clinical trial, hence, they play an excellent role in the spillover of pathogens. The main protease (6LU7) enzyme found in severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) is essential for viral replication. Thus, it acts as a hotspot in drug discovery. Objective: A molecular docking computational approach was used to determine the ability of the binding contract between the selected 3D-models of COVID-19 protease target and proposed natural compounds pristimerin, amazoquinone, kendomycin, celastrol, 20-epi-isoguesterinol, phenanthrenequinone, taxodione, maytenoquinone, hippeastrine, ammothamnine, 28-hydroxy isoiguesterin, hemanthamine, alisol-B, stigmasterol, β-pinene,and β-sitosterol through Autodock v.1.5.6 software. Method: The present study is designed to perform in-silico studies using molecular docking (Autodock tool v.1.5.6), Discovery Studio 2017 R2 client, Patch dock, SWISS-ADME prediction, and molecular simulation (Desmond simulation package of Schrodinger) between 6LU7 and natural origin compounds. Result: The results of docking study performed between 6LU7 and compounds pristimerin, amazoquinone, kendomycin, celastrol, 20-epi-isoguesterinol, phenanthrenequinone, taxodione, maytenoquinone, hippeastrine, ammothamnine, 28-hydroxy isoiguesterin, hemanthamine, alisol-B, stigmasterol, β-pinene, and β-sitosterol, showed binding energy as -9.68, -7.34, -5.34, -4.63, -4.24, -4.13, -4.08, -3.85, -3.83, -3.7, -3.6, -3.57, -3.54, -3.39, -3.18, and -3.03 Kcal/mol, respectively. It can be shown that the Pristimerin-6LU7 protein complex was maintained throughout the simulation since the ligand RMSDs varied with a maximum value of 4.2Å during the first 10 ns, followed by more stable interactions for the remaining time of the simulation. Conclusion: The goal of the current work was to find inhibitors for both prophylactic and therapeutic usage in COVID-19 patients.

Isolation of Verimol G from Illicium verum Hook.f. Fruit and its Computational Prediction as Antimalarial Agent

The present research focused on the isolation of the major compound in Illicium verum Hook.f. fruit and exploring its potential as an inhibitor of Plasmodium falciparum through computational approach, molecular docking and dynamic simulation. Verimol G was successfully extracted from the ethyl acetate extract for the first time from fruit. A successful prediction of the preferred orientation of the ligand to the receptor has been determined by the docking molecular approach. A molecular dynamics simulation was also conducted to study the dynamic behaviour of verimol G in relation to wild-type P. falciparum dihydrofolate reductase (PfDHFR). The free binding energy analyses (ΔGbind) of verimol G-PfDHRF was found to be -8.07 kcal mol-1. The decomposition energy results (ΔGbindresidue) showed that there were seven key binding residues which stabilized the binding of verimol G. The anticipated data could potentially serve as valuable insights for the advancement and formulation of an antiplasmodial medicine.

New amide and diterpene alkaloids with anticholinesterase activity from Delphinium cyphoplectrum roots.

The cholinergic hypothesis posits a robust correlation between the onset of Alzheimer's disease and a pronounced deficit in acetylcholine, a pivotal neurotransmitter crucial for the central cholinergic nervous system's function, pivotal for memory and learning. Diterpene alkaloids exhibit intricate and distinctive chemical structures that facilitate their passage through the blood-brain barrier. Moreover, their potent pharmacological attributes render them promising candidates for addressing central nervous system disorders. This investigation aims to scrutinize the alkaloidal composition of Delphinium cyphoplectrum (Ranunculaceae) roots, further exploring their anticholinesterase inhibitory activity and mode of inhibition. Innovative chromatography techniques were repetitively employed to purify the alkaloids. Acetylcholinesterase (AChE) inhibition assays were conducted using Ellman's tests. The mode of inhibition was meticulously characterized through Michaelis-Menten, and Lineweaver-Burk plots. Conducting molecular docking studies, we employed the AUTO DOCK 4.2 software package. Eight alkaloids were identified including five C19-diterpene alkaloids (6,14,16,18-tetramethoxy-1,7,8-trihydroxy-4-methylaconitane (1), 6,16,18-trimethoxy-1,7,8,14-tetrahydroxy-4-methylaconitane (2), 6,8,16,18-tetramethoxy-1,7,14-trihydroxy-4-methylaconitane (3), 6,14,16-trimethoxy-1,7,8,18-tetrahydroxy-4-methylaconitane (4), and 14-O-acetyl-8,16-dimethoxy-1,6,7,18-tetrahydroxy-4-methylaconitane (5)), an epoxy C18-diterpene alkaloid (6,8,16-trimethoxy-1,7,14-trihydroxy-3,4-epoxyaconitane (6)), a known (pyrrolidin-2-one (7) and an undescribed amide alkaloid (1-(2'-hydroxylethylamine)-3,5,5,-trimethyl-1,5-dihydro-2H-pyrrol-2-one (8). All diterpene alkaloids underwent assessment for acetylcholinesterase (AChE) inhibition assay and displayed noteworthy AChE activity, surpassing that of the reference drug (with IC50 values of 13.7, 21.8, 23.4, 28.2, 40.4, and 23.9 for compounds 1-6, respectively, in comparison to 98.4 for Rivastigmine). Analysis of Michaelis-Menten and Lineweaver-Burk plots represents an uncompetitive mode of inhibition for compound 1 on AChE. Notably, computational docking simulations indicated that all diterpene alkaloids were accommodated within the same enzymatic cleft as the reference ligand, and displaying superior free binding energy values (from - 10.32 to -8.59 Kcal.mol-1) in contrast to Rivastigmine (-6.31 Kcal.mol-1). The phytochemical analysis conducted on the roots of Delphinium cyphoplectrum yielded the identification of eight alkaloidal compounds including one C18-diterpene, five C19-diterpene, one pyrrolidine and one amide alkaloids. AChE inhibition assay and molecular simulations unveiled remarkable significant potency attributed to the C19-diterpene alkaloids by the order of 1 > 2 > 3,6 > 4 > 5. Presence of hydroxyl group on C-1, C-7, C-8, C-14, and C-18 increased the effect. The best in vitro activity was recorded for compound 1 able to bind to Asp72 in the narrow region of PAS, while interacting by pi-sigma with Phe330 at the hydrophobic region of the gorge involving the acyl and choline binding site. This observation underscores the substantial promise of this category of natural products in the realm of drug discovery for Alzheimer's Disease, offering a compelling avenue for further research and therapeutic development.

Molecular interactions by thermodynamic and computational molecular docking simulations of selected strawberry esters and pea protein isolate in an aqueous model system

The objective of this study was to determine the interactions between selected strawberry esters and pea protein isolate (PPI) in a protein-containing aqueous model system, utilizing modified ultrafiltration and equilibrium dialysis techniques. Strawberry esters, including ethyl butanoate, ethyl isopentanoate, ethyl hexanoate, and methyl anthranilate, demonstrated different binding parameters to the PPI. Overall flavor binding affinities (nK) of all esters decreased as the temperature increased from 5 °C to 25 °C. Among these compounds, ethyl hexanoate exhibited the highest affinity to PPI at 25 °C. Thermodynamic parameters revealed that all ester-PPI interactions were spontaneous and enthalpy-driven, primarily involving van der Waals forces or hydrogen bonding. In addition, computational molecular docking studies also identified alkyl hydrophobic interactions in ester-PPI complexes. These findings illustrated that understanding the interactions between esters and PPIs can assist in determining the optimal proportions of compounds for flavorings in high-protein beverages from pea protein.

Thermodynamic and functional changes of alpha-chymotrypsin after interaction with gallic acid

In the present study, the interaction mechanism between gallic acid (GA) and α-Chymotrypsin (α-CT) was investigated by employing a series ofspectroscopic methods, computational docking and molecular dynamic (MD) simulation. Fluorescence spectra analysis indicated the formation of a stable complex between GA and α-CT, where the quenching of the fluorescence emission was predominantly characterized by a static mechanism. TheCA obtained binding constants for the α-CT-GA complex were in the order of 103 M−1, indicating the moderate binding affinity of GA for α-CT. The corresponding CD findings showed that the interaction between GA and α-CT resulted in an alteration of the protein's secondary structure. The findings of the enzyme activity investigation clearly showed that the presence of GA led to a notable decline in the enzymatic activity of α-CT, highlighting GA's function as an effective inhibitor for α-CT. The molecular docking simulations revealed the optimal binding site for the GA molecule within the α-CT structure and MD simulations confirmed the stability of the α-CT-GA complex. This research expands our comprehension regarding the behavior of enzymes in the presence of small-molecule ligands and opens avenues for food safety.

Structural insights into the distinct substrate preferences of two bacterial epoxide hydrolases

Epoxide hydrolases (EHs), which catalyze the transformation of epoxides to diols, are present in many eukaryotic and prokaryotic organisms. They have recently drawn considerable attention from organic chemists owing to their application in the semisynthesis of enantiospecific diol compounds. Here, we report the crystal structures of BoEH from Bosea sp. PAMC 26642 and CaEH from Caballeronia sordidicola PAMC 26510 at 1.95 and 2.43 Å resolution, respectively. Structural analysis showed that the overall structures of BoEH and CaEH commonly possess typical α/β hydrolase fold with the same ring-opening residues (Tyr-Tyr) and conserved catalytic triad residues (Asp-Asp-His). However, the two enzymes were found to have significantly different sequence compositions in the cap domain region, which is involved in the formation of the substrate-binding site in both enzymes. Enzyme activity assay results showed that BoEH had the strongest activity toward the linear aliphatic substrates, whereas CaEH had a higher preference for aromatic- and cycloaliphatic substrates. Computational docking simulations and tunnel identification revealed important residues with different substrate-binding preferences. Collectively, structure comparison studies, together with ligand docking simulation results, suggested that the differences in substrate-binding site residues were highly correlated with substrate specificity.

A novel pyrazole derivative as COVID-19 main protease inhibitor: Synthesis, quantum computational studies, pharmacokinetic properties, drug likeness, molecular docking and dynamics simulation; a CADD approach

2-(3‑bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-8-methyl-4H benzo[d][1,3]oxazin-4-one (2-BCBO) compound, was synthesized by the reaction of 3‑bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid in acetonitrile and methane sulfonyl chloride. The monoclinic crystal structure in C2/c space group of the compound was unveiled through single-crystal X-ray diffraction studies. A prediction model was employed to investigate the influence of intermolecular contacts on molecular packing in the crystalline phase. The model incorporated both Hirshfeld surface and 2D fingerprint models to gain a comprehensive understanding of the strength of these contacts. The calculation of the total interaction energy was conducted by utilizing the three-dimensional molecular energy frameworks and further, employed density functional theory to examine molecular orbital characteristics and key factors associated with chemical reactivity. The application of topological analysis techniques, such as QTAIM and NCI, provided further insight regarding the attraction and repulsive interactions shown by the molecule. The pharmacokinetic properties of the 2-BCBO molecule have also been examined using ADMET analysis, which is important in drug discovery and development. In addition, the molecular docking study to determine the inhibitory effect of the investigated ligand on the main protease of new coronavirus (COVID-19), followed by molecular dynamics simulations, and it is found that both the results are in good agreement. The 2-BCBO could be accepted as a lead molecule to treat the coronavirus.