Docking Energy Research Articles

CSearch: chemical space search via virtual synthesis and global optimization

The two key components of computational molecular design are virtually generating molecules and predicting the properties of these generated molecules. This study focuses on an effective method for molecular generation through virtual synthesis and global optimization of a given objective function. Using a pre-trained graph neural network (GNN) objective function to approximate the docking energies of compounds for four target receptors, we generated highly optimized compounds with 300–400 times less computational effort compared to virtual compound library screening. These optimized compounds exhibit similar synthesizability and diversity to known binders with high potency and are notably novel compared to library chemicals or known ligands. This method, called CSearch, can be effectively utilized to generate chemicals optimized for a given objective function. With the GNN function approximating docking energies, CSearch generated molecules with predicted binding poses to the target receptors similar to known inhibitors, demonstrating its effectiveness in producing drug-like binders.Scientific Contribution We have developed a method for effectively exploring the chemical space of drug-like molecules using a global optimization algorithm with fragment-based virtual synthesis. The compounds generated using this method optimize the given objective function efficiently and are synthesizable like commercial library compounds. Furthermore, they are diverse, novel drug-like molecules with properties similar to known inhibitors for target receptors.

Rosiridin prevents cisplatin-induced renal toxicity by inhibiting caspase-3/NF-κB/ Bcl-2 signaling pathways in rats and in silico study.

The present investigation determines the effects of rosiridin in cisplatin (CP)-induced renal toxicity in rats. The experimental animals were used and divided into four groups. Experimental rats were randomly divided into group-I normal control, group-II CP group (8mg/kg i.p.), group-III CP + rosiridin (10mg/kg, p.o.) and group-IV rosiridin (10mg/kg p.o.). Various biochemical parameters, i.e., creatinine, urea, uric acid, cholesterol, blood urea nitrogen, antioxidant levels, inflammatory markers such as interleukins-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB), apoptosis markers including B cell lymphoma-2 (Bcl-2), caspase-3 and histopathological investigations were evaluated. Additionally, molecular docking and dynamics were performed to assess the interaction of rosiridin with target proteins. Rosiridin significantly minimized alteration in creatinine, urea, uric acid, cholesterol, blood urea nitrogen, antioxidant levels, and inflammatory, i.e., IL-1β, IL-6, TNF-α, NF-κB, Bcl-2, and caspase-3 which CP induced in rats. The interaction of rosiridin showed a favorable docking energy. The MD simulation results showed the higher stability of the complex generated from rosiridin. The current study exhibited rosiridin having a protective effect on CP-induced renal toxicity.

Unveiling the antimicrobial potentials of Sphagneticola trilobata: an integrated experimental and computer aided investigation

Although in the last three decades pharmaceutical industries invented good number of new drugs, resistance to antimicrobials is still prevailing due to the remarkable genetic plasticity of the microbes and drugs. In this present study, we have shown, Sphagneticola trilobata exhibited maximum zone of inhibition (20.5 ± 0.5 mm) and (20.166 ± 0.763 mm) against Streptococcus constellatus and Proteus sp. (in the case of human pathogenic bacteria) respectively and (27 ± 1mm) and (22.166 ± 0.763 mm) against Staphylococcus sciuri and Streptococcus dysgalactiae (in the case of human and animal pathogenic bacteria) respectively which were even greater than the zone of inhibition of the control. Additionally the minimum bactericidal concentration (MBC) and minimum inhibitory concentration (MIC) ratio of the plant extract was 2 or less (bactericidal) against all the tested bacterial strains. Moreover, the molecular docking studies of the compound list obtained from the Gas Chromatography Mass Spectrometry (GC-MS) analysis against Phosphoolipase C showed binding energy of −8.3Kcal/mol, −7.7Kcal/mol, and −7.5Kcal/mol respectively for CID-5318517, CID-6432640 and CID-6452077 compounds whereas sensor domain of Vbrk showed docking energy of −6.1Kcal/mol, −6.1Kcal/mol, and −6.4 Kcal/mol for CID-5318517, CID-6452077, and CID-13304974 respectively. Moreover, the CID-5318517, CID-11976203, CID-12313020 complexes exhibited the binding energy −6.7Kcal/mol, −6.1Kcal/mol, and −6.8Kcal/mol respectively while interacting with Sortase A protein. The pharmacological and bioactivity profiling showed no carcinogenic and toxic profiles along with more favourable drug properties. Our data showed the molecular geometries of the short listed compounds which proved their good molecular geometry towards the active sites of the microbial targets in DFT calculation and strong binding patterns for the docked complexes in multiple dynamics thresholds. However, these need to be further checked and additional experimental validations are required.

Enantioselective Metabolism of Mefentrifluconazole by Human Liver Microsomes.

A better understanding of the metabolic differences between chiral pesticide enantiomers in organisms is crucial for accurately assessing their risk. The enantioselective metabolism of mefentrifluconazole was investigated by the human liver microsome reaction system. The metabolic rate of S-mefentrifluconazole was found to be 4 times that of R-mefentrifluconazole. The chemical inhibitor method was used to further explore the cause of metabolic difference, and it was found that the inhibitors of CYP2C19 and CYP2C8 significantly reduced the metabolism of S-mefentrifluconazole (70.3-92.0%) and R-mefentrifluconazole (53.0-78.6%), respectively. CYP2C19 is a key metabolic enzyme of S-mefentrifluconazole. Molecular docking indicates that the internal energy of binding of R-mefentrifluconazole to CYP2C19 is too high, resulting in a positive docking fraction (0.1730 kJ/moL). Therefore, R-mefentrifluconazole cannot bind to CYP2C19 under natural conditions. CYP2C8 is the key metabolic enzyme of R-mefentrifluconazole. The lower docking energies (-37.80 kJ/moL for R-mefentrifluconazole and -35.64 kJ/moL for S-mefentrifluconazole) make CYP2C8 more capable of metabolizing R-mefentrifluconazole. This study provides essential data for exploring the toxicological assessment of mefentrifluconazole.

Integrated machine learning and physics-based methods assisted de novo design of Fatty Acyl-CoA synthase inhibitors

ABSTRACT Background Tuberculosis is an infectious disease that has become endemic worldwide. The causative bacteria Mycobacterium tuberculosis (Mtb) is targeted via several exciting drug targets. One newly discovered target is the Fatty Acyl-CoA synthase, which plays a significant role in activating the long-chain fatty acids. Research design & methods This study aims to generate novel compounds using Machine Learning (ML) algorithms to inhibit this synthase. Experimentally derived bioactive compounds were chosen from ChEMBL and used as inputs for effective molecule generation by Reinvent4. The library of new molecules generated was subjected to a two-tiered molecular docking protocol, and the results were further studied to obtain a binding free energy check. Results The ML-based de novo drug design (DNDD) approach successfully generated a diverse library of novel molecules targeting Fatty Acyl-CoA synthase. After rigorous molecular docking and binding free energy analysis, four new compounds were identified as potential lead candidates with promising inhibitory effects on Mtb lipid metabolism. Conclusions The study demonstrated the effectiveness of a machine-learning approach in generating novel drug candidates against Mtb. The identified hit compounds show potential as inhibitors of Fatty Acyl-CoA synthase, offering a new avenue for developing treatments for tuberculosis, particularly in combating drug-resistant strains.

Enantioseparation, Absolute Configuration, and Enantioselective Bioactivity Mechanism of the Chiral Fungicide Nuarimol.

In this study, the nuarimol enantiomers were successfully baseline separated with Rs 1.70 by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The absolute configurations of the nuarimol enantiomers were confirmed as R-(+)-nuarimol and S-(-)-nuarimol. The enantioselective bioactivity assay indicated that R-(+)-nuarimol exhibited greater potency against seven phytopathogenic fungi, with values approximately 1.4-3.5 and 4.5-51.4 times higher than those of rac-nuarimol and S-(-)-nuarimol. The active contribution value of R-enantiomer was 82-98%, showing that R-(+)-nuarimol played a crucial role in bioactivity. Meanwhile, R-(+)-nuarimol exhibited stronger effects in increasing the cell membrane permeability, compromising the cell membrane integrity, and inhibiting ergosterol biosynthesis. Molecular docking analysis showed that R-(+)-nuarimol possessed a stronger binding affinity to sterol 14-α demethylase (CYP51) than S-(-)-nuarimol, with docking energies of -7.42 and -7.36 kcal/mol. This study contributes essential data for screening a high-activity enantiomer of nuarimol and provide guidance for reducing used dosage and increasing the efficiency of nuarimolAQ.

In Silico Investigation of the Interactions Between Cotton Leaf Curl Multan Virus Proteins and the Transcriptional Gene Silencing Factors of Gossypium hirsutum L.

The highly dynamic nature of the Cotton leaf curl virus (CLCuV) complex (causing Cotton leaf curl disease, a significant global threat to cotton) presents a formidable challenge in unraveling precise molecular mechanisms governing viral-host interactions. To address this challenge, the present study investigated the molecular interactions of 6 viral proteins (Rep, TrAP, C4, C5, V2, and βC1) with 18 cotton Transcriptional Gene Silencing (TGS) proteins. Protein-protein dockings conducted for different viral-host protein pairs using Clustered Protein Docking (ClusPro) and Global RAnge Molecular Matching (GRAMM) (216 docking runs), revealed variable binding energies. The interacting pairs with the highest binding affinities were further scrutinized using bioCOmplexes COntact MAPS (COCOMAPS) server, which revealed robust binding of three viral proteins- TrAP, C4, and C5 with 14 TGS proteins, identifying several novel interactions (not reported yet by earlier studies), such as TrAP targeting DCL3, HDA6, and SUVH6; C4 targeting RAV2, CMT2, and DMT1; and C5 targeting CLSY1, RDR1, RDR2, AGO4, SAMS, and SAHH. Visualizing these interactions in PyMol provided a detailed insight into interacting regions. Further assessment of the impact of 18 variants of the C4 protein on interaction with CMT2 revealed no correlation between sequence variation and docking energies. However, conserved residues in the C4 binding regions emerged as potential targets for disrupting viral integrity. Hence, this study provides valuable insights into the viral-host interplay, advancing our understanding of Cotton leaf curl Multan virus pathogenicity and opening novel avenues for devising various antiviral strategies by targeting the host-viral interacting regions after experimental validation.

Anticancer activity of the synthetic kusunokinin analogues on human cancer cell lines

The series of racemic kusunokinin derivatives were synthesized and their cytotoxic activities and cell viability on cancer cells including breast cancer (MCF-7, MDA-MB468), colon cancer (HT-29), cholangiocarcinoma (KKU-M213) and ovarian cancer (A2780) cells were investigated. The results showed that compounds 6aa, 6da, and 6de exhibited growth inhibition against breast cancer (MDA-MB468), cholangiocarcinoma (KKU-M213), colon cancer (HT-29), and ovarian cancer (A2780) cells with IC50 values (μM) 13.77 ± 0.38, 7.94 ± 0.45, and 4.22 ± 0.13 (MDA-MB468); 4.21 ± 0.21, 0.97 ± 0.03, and 0.09 ± 0.02 (KKU-M213); 22.66 ± 0.23, and 15.62 ± 0.06 (HT-29); 13.11 ± 0.37, 11.51 ± 0.43, and 1.87 ± 0.01 (A2780); respectively. Interestingly, a positive control, doxorubicin, showed less cytotoxicity than 6da and 6de on cholangiocarcinoma KKU-M213 and ovarian cancer A2780 cells. Moreover, these three synthetic compounds also exhibited less toxicity than doxorubicin on the normal cells, MMNK-1, Vero and L-929. The binding possibility towards CSF1R, 6de (−11.59 kcal/mol) and trans-(−)-kusunokinin (−11.75 kcal/mol) were similar in both docking energies and docking poses. 6de interacted with Trp550 via π-π stacking in the similar manner with trans-(−)-kusunokinin and trans-(+)-kusunokinin.

Pyrazole Amides Towards Trailblazing Antimicrobial Research: Bridging in Vivo Insights and Molecular Docking Studies

Antimicrobial resistance presents a significant threat to contemporary healthcare systems, making it increasingly difficult to treat infections that were once easily managed. This study aims to assess the efficacy of pyrazole benzamide derivatives (M5a–M5o), which were synthesized for their antimicrobial and antifungal activities. These compounds were tested against methicillin resistant staphylococcus aureus (MRSA), vancomycin resistant staphylococcus aureus (VRSA), mycobacterium tuberculosis H37Rv and other resistant species. The minimum inhibitory concentrations (MIC) were determined using standardized protocols to evaluate their potency and effectiveness. Molecular docking studies were also conducted to explore potential interactions and binding affinities at the molecular level, providing further insights into their antimicrobial and anti-tubercular mechanisms. Compounds M5i, M5k, and M5b emerged as the most potent, displaying MIC value of 3.12 μg/ml. These compounds show great potential as new agents in addressing the growing problem of antimicrobial resistance. Molecular docking studies against Enoyl-[acyl-carrier-protein] reductase (4DRE), revealed key interactions, with compound M5n showing a docking energy of -9.8 kcal/mol and compound M5g at -9.6 kcal/mol. These compounds formed important hydrogen bonds and π-interactions with residues like Lys165, Gly14, Ser94, and Ile21. Overall, the findings indicate that specific pyrazole-benzamide derivatives exhibit promising antimicrobial and antifungal activities, underscoring their potential as therapeutic agents. Additionally, the integration of molecular docking studies proves valuable in guiding the development and optimization of these compounds for future therapeutic applications.

The molecular reactive pathway between lipoxygenase and lipase and reactive species generated in dielectric barrier discharge atmospheric cold plasma: An investigation using molecular docking

The molecular docking was explored to study the interactions between reactive species generated by cold plasma and the enzymes lipoxygenase (LOX) and lipase (LPS), with the aim of elucidating the molecular mechanisms governing these interactions. Molecular docking results suggest that both LOX and LPS are primarily involved in hydrogen bonding interactions with the seven reactive species. The key binding sites for LOX and LPS were identified as Ile 663 and Glu 188, respectively. Notably, the lowest docking energy was observed between LOX and NO (−13.75 kcal/mol), whereas for LPS, it is between LPS and NO3 (−12.08 kcal/mol). Increased treatment voltage and time resulted in higher inactivation levels, with LPS exhibiting higher residual activity compared to LOX. When the voltage was 75 kV and the time was 120 s, the residual activities of LOX and LPS were 42.88% and 56.77%, respectively. Consequently, the results enhance our understanding of the mechanisms underlying the inhibition of enzyme activity by reactive species generated by cold plasma. Moreover, cold plasma may serve as a novel preservation technology for inhibiting lipid oxidation of food by controlling enzyme activity.

Identification and anticoagulant mechanisms of novel factor XIa inhibitory peptides by virtual screening of a in silico generated deep-sea peptide database

The objective of this study was to identify novel anticoagulant peptides from the deep-sea using multiple in silico methods, and to investigate their inhibitory activity and molecular mechanisms. A deep-sea peptide database was firstly constructed by performing virtual proteolysis on protein sequences from animals inhabiting deep-sea hydrothermal vents and cold seeps. Candidate anticoagulant peptides were identified through molecular docking and binding free energy screening against FXIa as the target. Two novel anticoagulant peptides, PRNIF (IC50 = 0.67 mM) and GNDRCL (IC50 = 1.52 mM), were identified, and their anticoagulant activities were verified in vitro. PRNIF was demonstrated to be a noncompetitive inhibitor of FXIa, and caused significant prolongation of thrombin time (TT) and activated partial thromboplastin time (APTT), whereas GNDRCL markedly prolonged the APTT only. Molecular dynamics simulations demonstrated considerable conformational shifts of both anticoagulant peptides when bound to the active sites of FXIa. The lowest energy binding poses of the FXIa-peptide complexes for PRNIF and GNDRCL exhibited comparable numbers of hydrogen bonds and binding free energies. However, occupancy analysis revealed completely distinct stability characteristics of the hydrogen bond interactions. The conserved residue Asp569 in the S1 pocket of FXIa formed strong and stable hydrogen bonds as well as a salt bridge with the arginine residues of PRNIF, which were not observed in the FXIa-GNDRCL complex. To our knowledge, PRNIF represented the first FXIa inhibitory peptide derived from the deep-sea, which may contribute to the development and utilization of deep-sea peptides resources. Two deep-sea peptides may potentially serve as an alternative food-derived ingredient that could be utilized for thrombosis prevention.

Physics statistical analysis of crystal violet adsorption onto activated bamboo fiber powder: Insights from thermodynamic functions

This current research scrutinizes the adsorption behavior of Crystal Violeton Activated Bamboo Fiber Powder (ABFP)for water purification. By leveraging four advanced statistical physics scenarios (Hill framework with single energy, Hill framework with dual-energy, Double-layer framework with single energy and Double-layer framework with dual energy), experimental data is meticulously fitted to elucidate the surface adhesion phenomenon by uncovering its decisive influencing metrics.Four convergence criteria (R2, RMSE, AIC and RSS) have been employed to identify the most accurate model while steriographic along with energetic-thermodynamic metrics have been inspected in response to combined effects of temperature and concentration. Major outcomes revealed that the fourth scenario exhibits the most favorable agreement with the measured points. The spatial arrangement factor n varied from 0.58 to 0.75 indicating that the dye retention can occur via two different orientations (parallel and non-parallel) with different percentages. In addition, the adsorption amounts at temperatures of 298, 308 and 318 K were 1403.13, 1365.75 and 1270.79 mg/g, respectively, revealing the exothermicity of crystal violet adsorption onto the pores of Activated Bamboo Fiber Powder. The estimated docking energies were below 40 kJ/mol, suggesting that physical forces primarily govern the surface attachment. Assessment of enthalpy and Gibbs free energy demonstrated that the adsorption process occursfeasibly, spontaneously and is accompanied by heat release. The pore size distribution (PSD) of (ABFP) are determined. Since, the Activated Bamboo Fiber Powder (ABFP) showed promising results for competitive adsorption, thus being of relevance to the industrial sector.

Phytochemical Profiling and Anti-VanA Activity of Pulegone Extracted from Ziziphora tenuior Flower Against Vancomycin-Resistant Enterococci: an In Silico Approach.

Ziziphora tenuior is a herb known for its potent pharmaceutical activities. However, the specific compounds of the flowers of this herb have not been fully studied yet. This study used GC-MS to conduct a chemical analysis of the methanol and dichloromethane extracts of Z. tenuior flowers. Additionally, it sought to assess the potential antibacterial activity of the extracts against vancomycin-resistant enterococci (VRE) bacteria by predicting the interactions between one of the most prevalent compounds in the extracts and the D-alanyl-D-lactate ligase (VanA) protein, which is responsible for enterococci resistant to vancomycin. The results revealed a total of 15 compounds in the methanolic extract and 12 compounds in the dichloromethane extract. Among these, 5-methyl-2-(1-methylethylidene)-cyclohexanone, also known as pulegone, constituting 52.6 % of the methanolic extract and 34.6 % of the dichloromethane extract, was the most abundant compound in the extracts. Furthermore, the in-silico analysis demonstrated that pulegone exhibited significant interactions with VanA, as indicated by docking energy values of -7 kcal/mol and the formation of one hydrogen bond. The study suggests that pulegone shows promise as an antibacterial agent against VRE by potentially interacting with VanA protein and serving as a key inhibitor in fighting vancomycin resistance.

Virtual screening, ADMET prediction, molecular docking, and dynamic simulation studies of natural products as BACE1 inhibitors for the management of Alzheimer’s disease

Alzheimer’s disease (AD) is a degenerative neurological disorder that chronically and irreversibly affects memory, cognitive function, learning ability, and organizational skills. Numerous studies have demonstrated BACE1 as a critical therapeutic target for AD, emphasizing the need for specific inhibition of BACE1 to develop effective therapeutics. However, current BACE1 inhibitors have certain limitations. Therefore, the aim of this study was to identify potential novel candidates derived from natural products that can be utilized for the treatment of AD. To achieve this, 80,617 natural compounds from the ZINC database were subjected to virtual screening and subsequently filtered according to the rule of five (RO5), leading to the identification of 1,200 compounds. Subsequently, the 1,200 compounds underwent molecular docking studies against the BACE1 receptor, utilizing high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) techniques to identify high-affinity ligands. Of the 50 ligands that exhibited the highest G-Scores in HTVS, further analysis was conducted using SP docking and scoring methods. This analysis led to the identification of seven ligands with enhanced binding affinities, which were then subjected to additional screening via XP docking and scoring. Finally, the stability of the most promising ligand in relation to BACE1 was assessed through molecular dynamics (MD) simulations. The computational screening demonstrated that the docking energy values for seven ligands binding to target enzymes ranged between − 6.096 and − 7.626 kcal/mol. Among these, ligand 2 (L2) exhibited the best binding energy at -7.626 kcal/mol with BACE1. MD simulations further confirmed the stability of the BACE1-L2 complex, emphasizing the formation of a robust interaction between L2 and the target enzymes. Additionally, pharmacokinetic and drug-likeness evaluations indicated that L2 is non-carcinogenic and able to permeate the blood-brain barrier (BBB). The findings of this study will contribute to narrowing down the selection of candidates for subsequent in vitro and in vivo testing.

Identification of a Novel HIV‐1 Integrase Strand Transfer Inhibitor: A Synergistic Approach Combining Pharmacophore Modelling and In Vitro Assays

BackgroundAIDS is a highly prevalent and life‐threatening global epidemic that severely compromises the host's immune system, increasing vulnerability to opportunistic diseases. The absence of definitive curative drugs emphasizes the importance and necessity of discovering novel anti‐HIV agents.ObjectiveThis study aims to discover a natural molecular entity that acts as an Integrase strand transfer inhibitor (INSTI) with enhanced potency against HIV.MethodsA ligand‐based pharmacophore model was developed for 4 FDA‐approved INSTIs, with the potential for treating HIV‐1. AutoDock facilitated molecular docking and free energy calculation to discern IN activity. Subsequently, MD simulations assessed interaction stability. ADMET analysis preceded an in vitro anti‐HIV strand transfer assay.ResultsThe generated model revealed a specific interaction involving Mg2+ ion chelation. Crucial residues of HIV‐1 IN and their respective free‐binding energies were identified. The lead compound exhibited superior in silico characteristics which were substantiated by 100 ns MD simulations and MM‐PBSA analysis. Additionally, the in vitro assay demonstrated potent inhibition with the lowest IC50, forming strong molecular interactions with IN.ConclusionThese findings showed valuable insights for the strategic development of new antiretroviral treatments (ART), paving the path for the development of natural therapeutic agents for HIV treatment.

Identification of optimal laccases for chlorinated phenol degradation: Insights from molecular modelling, docking, dynamics, and free energy calculations

This study aimed to investigate the interactions between twenty different bacterial and fungal laccases and chlorinated phenols (CPs), which are listed as priority pollutants by the United States Environmental Protection Agency (USEPA). Molecular docking was used to identify the optimal laccase for degrading CPs out of twenty selected laccases to save time and reduce the in vitro selection of laccase for CPs degradation. The average binding energies of CPs with bacterial and fungal laccases were − 4.72 kcal/mol and − 5.21 kcal/mol, respectively. Based on the highest average binding energies Trametes versicolor (fungus) and Xanthomonas arboricola (bacteria) laccase apo and bound forms were investigated for stability and interaction dynamics using a 200 ns molecular dynamic simulation. The root mean square deviations (RMSD) of T. versicolor and X. arboricola laccase bound forms were within the 0.25 nm and 0.5 nm limit. The radius of gyration (Rg) for all laccases bound forms remained within the range from 1.88 to 2.24 nm with majority of residues in root mean square fluctuations (RMSF) were within the 0.24 nm and found consistent with the laccase apo values. In an aqueous solution, at ∼300 K and ∼ 1 bar pressure, laccase stability with CPs is facilitated by hydrophobic interactions, hydrogen bonds, and van der Waals forces. The corresponding computational insights will be advantageous for the selection, design and application in engineering of laccases for in vitro CPs degradation.

Integrating network pharmacology and experimental verification to explore the pharmacological mechanisms of Guanxin Shutong capsule in treating heart failure.

The Guanxin Shutong capsule (GXST), a traditional Chinese medicine, is commonly used for treating cardiovascular disease, it has shown efficacy in improving symptoms and enhancing the quality of life for patients with heart failure (HF). However, the specific mechanism of action of GXST in HF remains unclear. In this study, we employed a comprehensive approach combining network pharmacology, molecular dynamics (MD) simulations, and in vitro validations to investigate the potential targets and molecular mechanisms of GXST against HF. We collected active ingredients and target genes of GXST, as well as related genes of HF, from multiple public databases. Using bioinformatics analysis, we constructed networks of ingredients-disease-targets and performed functional annotations of the core targets. MD simulations were conducted to verify the binding between the core protein-ligand complexes. In vitro evaluations, including cell proliferation, apoptosis, and protein expression in human umbilical vein endothelial cells (HUVECs) and H9C2 cells were treated with GXST, were performed for pharmacodynamics evaluation. Network analysis revealed 320 intersection genes and 74 active ingredients in the Herbs-ingredients-target genes-disease network. We identified key active ingredients and target genes that overlapped. The KEGG pathways of the intersection genes were primarily enriched in the PI3K-Akt signaling pathway and apoptosis. The protein-protein interaction network highlighted proteins such as AKT1, VEGFR2, and eNOS. MD simulations confirmed stable docking and lower binding energy between 4 identified ingredients (kaempferol, quercetin, (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl) chroman-4-one, and ellagic acid) and their respective core proteins (VEGFR2, eNOS, and AKT). In vitro experiments demonstrated the protective effects of GXST against H2O2-induced apoptosis in both HUVECs and H9C2 cells. Notably, consistent with the in silico predictions, GXST effectively activates the VEGFR2/AKT/eNOS signaling pathways in HUVECs. This study provides insights into the underlying mechanism of GXST's therapeutic effects in heart failure. The involvement of the VEGFR2/AKT/eNOS signaling pathways suggests their importance in further elucidating and applying GXST in the clinical treatment of heart failure.

Structural analysis and theoretical studies of 2-(2-chlorobenzylidene) malononitrile (CS) “a riot controlling agent”

In solvent methanol, malononitrile and 2-chlorobenzaldehyde were stirred in the presence of base piperidine to synthesise the target chemical 2-(2-chlorobenzylidene) malononitrile (CS). The crystal structure of the target compound C10H5ClN2 has been elucidated through X-ray crystallographic analysis. It crystallises in the monoclinic crystal system within the P21 space group, containing four molecules per asymmetric unit. The unit cell dimensions are a = 3.8825(3) Å, b = 21.0202(18) Å, c = 21.3481(18) Å, and β = 95.096(4)°. The phenyl and malononitrile groups, which make up the molecular components, are each planar but slanted towards one another at a dihedral angle of 12.7° (4). Besides this, target molecule is also stabilized by hydrogen bonding, halogen bonding and π stacking interactions. Solid-state structure has been analysed through Hirshfeld surface analysis, including the evaluation of the different energy frameworks, indicating that the molecular sheets are primarily formed by hydrogen bonds and halogen bonds and the stabilization is dominated via the electrostatic energy contribution. Fingerprint plots were carried out to study the relative contribution of noncovalent interactions in the target compound CS. Further, the density functional theory calculations were employed using B3LYP hybrid functional with 6-311++G level basic set to optimize the structural coordinates in gas phase and in different solvents (chloroform, water, and methanol). The chemically active regions of the target compound were identified by the analysis of molecular electrostatic potential surface. Further, from PASS analysis and literature reports, molecular docking of title compounds was carried out with human transient receptor potential ankyrin 1 ion channel (hTRPA1) (PDB-ID 6PQO). ΔGb (docking energy) and inhibition constant was calculated to be −7.53 kcal/mol and 3.33 μM respectively, with the target ion channel.

Investigating the Inhibitory Potential of Flavonoids against Aldose Reductase: Insights from Molecular Docking, Dynamics Simulations, and gmx_MMPBSA Analysis.

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, with aldose reductase playing a critical role in the pathophysiology of diabetic complications. This study aimed to investigate the efficacy of flavonoid compounds as potential aldose reductase inhibitors using a combination of molecular docking and molecular dynamics (MD) simulations. The three-dimensional structures of representative flavonoid compounds were obtained from PubChem, minimized, and docked against aldose reductase using Discovery Studio's CDocker module. The top 10 compounds Daidzein, Quercetin, Kaempferol, Butin, Genistein, Sterubin, Baicalein, Pulchellidin, Wogonin, and Biochanin_A were selected based on their lowest docking energy values for further analysis. Subsequent MD simulations over 100 ns revealed that Daidzein and Quercetin maintained the highest stability, forming multiple conventional hydrogen bonds and strong hydrophobic interactions, consistent with their favorable interaction energies and stable RMSD values. Comparative analysis of hydrogen bond interactions and RMSD profiles underscored the ligand stability. MMPBSA analysis further confirmed the significant binding affinities of Daidzein and Quercetin, highlighting their potential as aldose reductase inhibitors. This study highlights the potential of flavonoids as aldose reductase inhibitors, offering insights into their binding interactions and stability, which could contribute to developing novel therapeutics for DM complications.

In Silico Analysis of Vitamin D Interactions with Aging Proteins: Docking, Molecular Dynamics, and Solvation Free Energy Studies

Aging is a natural process that is also influenced by some factors like the food someone eats, lifestyle decisions, and impacts on general health. Despite the recognized role of nutrition in modulating the molecular and cellular mechanisms underlying aging, there is a lack of comprehensive exploration into potential interventions that can effectively mitigate these effects. In this study, we investigated the potential anti-aging properties of vitamin D by examining its interactions with key molecular targets involved in aging-related pathways. By using molecular docking and dynamics techniques, we evaluate the interactions and stability of vitamins D2 and D3 with key proteins involved in aging pathways, such as SIRT1, mTOR, AMPK, Klotho, AhR, and MAPK. Our results reveal promising binding affinities between vitamin D and SIRT1 forms, with energy values of −48.33 kJ/mol and −45.94 kJ/mol for vitamins D2 and D3, respectively, in aqueous environments. Moreover, molecular dynamics simulations revealed that the vitamin D3–SIRT1 complex exhibited greater stability compared with the vitamin D2–SIRT1 complex. The study calculated the solvation free energy to compare the solubility of vitamins D2 and D3 in water and various organic solvents. Despite their strong interactions with water, both vitamins exhibited low solubility, primarily due to the high energy cost associated with cavity formation in the aqueous environment. Compared with other solvents, water demonstrated particularly low solubility for both vitamins. This suggested that vitamins D2 and D3 preferred binding to aging receptors over dissolving in bulk aqueous environments, supporting their strong therapeutic interactions with these receptors. These findings shed light on the molecular mechanisms underlying vitamin D’s potential anti-aging effects and lay the groundwork for developing nutraceuticals targeting aging and associated diseases. Understanding these mechanisms holds promise for future interventions aimed at promoting healthy aging and enhancing overall well-being.