High Binding Free Energy Research Articles

α-GLUCOSIDASE AND TYROSINASE INHIBITORY GUIDED ISOLATION, IDENTIFICATION OF MAJOR COMPOUND AND IN SILICO STUDY FROM EDIBLE MUSHROOM COPRINUS COMATUS

Coprinus comatus is an edible and medicinal mushroom. The crude hexane, EtOAc and methanol extracts were extracted successively from C. Comatus. All the crude extracts were evaluated for anti-a-glucosidase and tyrosinase. The results showed that %inhibition valued for the crude hexane, EtOAc and methanol extracts of anti-a-glucosidase were 98.58 ± 0.09, 98.90 ± 0.21, and 6.68 ± 0.79, respectively. The anti-tyrosinase for the crude hexane, EtOAc and methanol extracts were 97.31 ± 2.77, 97.31 ± 3.34 and 64.94 ± 3.34, respectively. Notably, the bioassay-guided showed that the crude hexane and EtOAc were the highest for anti-a-glucosidase and tyrosinase activities, which led to the interest in purifying the major compound. The isolation and purification were successively done using chromatographic techniques. The pure compounds were determined by spectroscopic analysis (UV, FTIR, and NMR) and comparison with previously reported. The isolation led to three compounds (1-3), ergosterol (1), indole-3-carbaldehyde (2), and 4-hydroxybenzoic acid (3). The molecular docking of compounds 1-3, reported as α-glucosidase and tyrosinase inhibitors, was done by the AutoDockTools 1.5.6 (ADT) software. The results revealed that ergosterol (1) provides the highest binding free energy (-9.91 kcal/mol) to the active site of a-glucosidase, indicating that it is quite specific to this enzyme. Moreover, ergosterol (1) has strong binding energy (-9.64 kcal/mol) to tyrosinase but not significant tyrosinase specificity. This evidence supports that C. Comatus would be applicable for a functional food for controlling glucose blood levels.

Exploring the factors influencing the ketoenamine-enolimine tautomeric equilibrium of pyridoxal 5′-phosphate in branched-chain aminotransferases

Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, is a critical coenzyme for various enzymes. It generates a Schiff base with the substrate and exhibits ketoenamine and enolimine tautomeric forms due to intramolecular proton transfer. This study aims to ascertain the predominant tautomeric form of the PLP Schiff base in MtIlvE and analyze its influencing factors. Molecular dynamics simulations indicate that the ketoenamine tautomer has higher binding free energy than the enolimine tautomer. Density functional theory calculations suggest that, despite their ability to interconvert at a relatively low energy barrier, the ketoenamine tautomer is thermodynamically more stable. Factors affecting the keto-enol tautomeric equilibrium were investigated by constructing various QM-cluster models. Our results demonstrate that both the protonation of the pyridine nitrogen and the presence of Tyr209, which stabilizes the O3 anion, shift the tautomeric equilibrium toward the ketoenamine configuration. These findings provide a theoretical basis for investigating enzyme catalytic mechanisms.

In silico studies of thiazole derivative towards its potential use against SARS-CoV-2: An intuition from an experimental and computational approach

The N-(4-methoxyphenyl)-4-phenylthiazole-2-carboxamide (TT7) obtained via cyclization of methyl 2-((4-methoxyphenyl)amino)-2-oxoethanedithioate with ɑ-haloketone and then characterized by 1H-NMR and 13C-NMR spectroscopy, and single crystal X-ray diffraction method. Weak intermolecular interactions like C-H...O, C-H...π, C-O...π, and π...π interactions help to stabilize the compound TT7. The weak interactions formed in the solid structure of the compound TT7 were meticulously investigated using theoretical approach like Hirshfeld surface analysis using crystallographic information file (.cif). Further, the density functional theory calculations have been performed to obtain the optimized geometry of the structure, and to explore the electronic properties of the molecule. The charge distribution on the molecular surface is analyzed by the molecular electrostatic potential (MEP) map. QTAIM and RDG analyses were done to explore the weak interactions (intramolecular) in the compound TT7 in the gaseous phase. The compound TT7 displayed good in silico results against SARS-CoV-2 main protease. Molecular docking study on SARS-CoV-2 virus major protease (PDB IDs: 6LZE and 6LU7) shows higher docking scores. Molecular dynamics simulations confirmed the inhibitory action of the newly synthesized compound (TT7). The binding free energy and contributed energies were determined using the MM-GBSA technique. The 6LU7-ligand complex has the highest binding free energy, with considerable contributions from covalent and van der Waals interactions.

Computational Insights Into the Mechanism of EGCG's Binding and Inhibition of the TDP-43 Aggregation.

Misfolding and aggregation of TAR DNA-binding protein, TDP-43, is linked to devastating proteinopathies such as ALS. Therefore, targeting TDP-43's aggregation is significant for therapeutics. Recently, green tea polyphenol, EGCG, was observed to promote non-toxic TDP-43 oligomer formation disallowing TDP-43 aggregation. Here, we investigated if the anti-aggregation effect of EGCG is mediated via EGCG's binding to TDP-43. In silico molecular docking and molecular dynamics (MD) simulation suggest a strong binding of EGCG with TDP-43's aggregation-prone C-terminal domain (CTD). Three replicas, each having 800 ns MD simulation of the EGCG-TDP-43-CTD complex, yielded a high negative binding free energy (ΔG) inferring a stable complex formation. Simulation snapshots show that EGCG forms close and long-lasting contacts with TDP-43's Phe-313 and Ala-341 residues, which were previously identified for monomer recruitment in CTD's aggregation. Notably, stable physical interactions between TDP-43 and EGCG were also detected invitro using TTC staining and isothermal titration calorimetry which revealed a high-affinity binding site of EGCG on TDP-43 (Kd, 7.8 μM; ΔG, -6.9 kcal/mol). Additionally, TDP-43 co-incubated with EGCG was non-cytotoxic when added to HEK293 cells. In summary, EGCG's binding to TDP-43 and blocking of residues important for aggregation can be a possible mechanism of its anti-aggregation effects on TDP-43.

Probing the role of hydrogen bond donors on the speciation and electrochemical behavior of Eu(III) in choline chloride-based DESs

This study explores the electrochemical properties and speciation of Eu(III) ions in choline chloride (ChCl)-based deep eutectic solvents (DESs), focusing on how different hydrogen bond donors—urea (U), ethylene glycol (EG), and malonic acid (MA)—influence the stability of europium complexes. Employing electrochemical methods, spectroscopic analysis, and theoretical approaches, the research examines how changes in hydrogen bonding during complexation affect Eu(III) coordination. Cyclic voltammetry highlights the role of complex formation and DES viscosity in controlling mass transport and electron transfer rates. Theoretical and experimental data show that the ChCl:1MA DES forms the most stable europium complex, driven by strong hydrogen bonding and robust Eu-DES interactions, as supported by optimized geometries and favorable electrochemical stability. This stability is further confirmed by the high negative binding and formation free energies of Eu(NO3)3·5H2O in all three DES systems. Photoluminescence spectroscopy reveals fluorophore formation due to interactions between hydrogen bonds and functional groups such as –NH2, –COOH, and –OH, enhancing the understanding of Eu3+-DES complexes for potential applications in materials science. By clarifying how hydrogen bond donors affect Eu(III) speciation and reactivity, this research advances lanthanide chemistry in DESs and opens avenues for designing Eu(III)-based materials with specialized properties for various technological uses.

Thymus algeriensis essential oil: Phytochemical investigation, bactericidal activity, synergistic effect with colistin, molecular docking, and dynamics analysis against Gram-negative bacteria resistant to colistin

Due to the increasing resistance prevalence to the last line of antibiotics, such as colistin, and the rising threat of multi-drug resistant bacteria, it is crucial to find alternative therapeutic options. The current study focuses on evaluating antibacterial activities alone and in combination with colistin of Thymus algeriensis essential oil (TA-EO) against colistin-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli co-harboring mcr-1 gene. GC/MS was used to determine the chemical composition of TA-EO. Disc diffusion and microdilution techniques were used to evaluate the antimicrobial activities of TA-EO. Synergism between colistin and TA-EO was evaluated by checkerboard assay. The major compounds of TA-EO were docked with known enzymes involved in resistance to colistin, as well as the biosynthesis of peptidoglycan and amino acids. GC/MS revealed that TA-EO was of carvacrol chemotype (67.94 %). The TA-EO showed remarkable antibacterial activities against all Gram-negative bacterial strains, with the diameter of inhibition zones varied between 30 and 50 mm and a ratio MBC/MIC equal to 1 for the vast majority of bacterial isolates. Interestingly, the checkerboard showed synergism between TA-EO and colistin against colistin-resistant Escherichia coli co-harboring mcr-1 gene (FICI˂1) and reduced the MIC of colistin by 16- to 512-fold and those of TA-EO by 4- to 16-fold. The docking study demonstrated that carvacrol had high binding free energies against MCR-1, a phosphoethanolamine transferase extracellular domain, and its catalytic domain implicated in resistance to colistin, and undecaprenyl pyrophosphate synthase in complex with magnesium which is involved in bacterial peptidoglycan biosynthesis. The molecular dynamics study for 100-ns also revealed the stability of the MCR-1/carvacrol complex with a constant surface area over the simulation. These results support using carvacrol or TA-EO as a bactericidal agent, either alone or in combination with colistin, to treat infections caused by colistin-resistant Gram-negative bacteria.

Cheminformatics-based analysis identified (Z)-2-(2,5-dimethoxy benzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one as an inhibitor of Marburg replication by interacting with NP

The highly pathogenic Marburg virus (MARV) is a member of the Filoviridae family, a non-segmented negative-strand RNA virus. This article represents the computer-aided drug design (CADD) approach for identifying drug-like compounds that prevent the MARV virus disease by inhibiting nucleoprotein, which is responsible for their replication. This study used a wide range of in silico drug design techniques to identify potential drugs. Out of 368 natural compounds, 202 compounds passed ADMET, and molecular docking identified the top two molecules (CID: 1804018 and 5280520) with a high binding affinity of −6.77 and −6.672 kcal/mol, respectively. Both compounds showed interactions with the common amino acid residues SER_216, ARG_215, TYR_135, CYS_195, and ILE_108, which indicates that lead compounds and control ligands interact in the common active site/catalytic site of the protein. The negative binding free energies of CID: 1804018 and 5280520 were −66.01 and −31.29 kcal/mol, respectively. Two lead compounds were re-evaluated using MD modeling techniques, which confirmed CID: 1804018 as the most stable when complexed with the target protein. PC3 of the (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) was 8.74 %, whereas PC3 of the 2′-Hydroxydaidzein (CID: 5280520) was 11.25 %. In this study, (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) unveiled the significant stability of the proteins' binding site in ADMET, Molecular docking, MM-GBSA and MD simulation analysis studies, which also showed a high negative binding free energy value, confirming as the best drug candidate which is found in Angelica archangelica which may potentially inhibit the replication of MARV nucleoprotein.

Synthesis, QTAIM, anticancer activity analysis of pyrrole-imidazole/benzimidazole derivatives and investigation of their reactivity properties using DFT calculations and molecular docking

As part of our ongoing investigation into pyrrole derivatives, we here present the synthesis, spectroscopic characterization, QTAIM, reactivity, anticancer activity, and comparative experimental and computational analysis of pyrrole-imidazole ((3l), (3p)) and benzimidazole derivatives ((3h), (3i), (3j), (3k), (3m), (3n), (3o)). All synthesized compounds (3h-3p) have been well characterized by spectroscopic techniques (FT-IR, 1H and 13C NMR, Mass spectrometry). The experimental 1H and 13C NMR chemical shift values of synthesized pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives have been well corroborated with computed chemical shifts. The vibrational analysis for four derivatives of pyrrole-benzimidazole (3m), (3n), (3o), and pyrrole-imidazole (3p) has the suitability for dimer formation in solid state by intermolecular heteronuclear hydrogen bonding (N–H···O) and the interaction energy of dimers are calculated to be 10.88, 11.70, 9.89 and 10.72 kcal/mol, using DFT. After basis-set superposition error (BSSE) correction, the interaction energies of dimers were found to be 11.12, 12.11, 10.13, and 11.52 kcal/mol. Estimated intermolecular H-bond in (3m-3n) compounds were found to be -13.38, -12.86, -11.02, and -11.28 kJ/mol using QTAIM. All the synthetic pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives exhibit strong antileukemia activity in vitro against the proliferative cell line L1210 leukemia cells. A dataset of investigated compounds was subjected for molecular modelling simulation against three distinct proteins (SYK, PI3K, and BTK), which was found to be highly implicated in the favourable interaction between the compounds and their target proteins in every instance. The synthesized pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives shown favourable interactions with their target proteins, with high activity and binding free energy values falling between 15.22 and 13.43 and -7.4 and -9.8 kcal/mol, respectively. The structure of pyrrole-imidazole (3l, 3p) and benzimidazole (3h-3o) derivatives is thoroughly examined, and several parameters are proposed here to improve their anticancer activity.

Screening and Evaluation of Potential Efflux Pump Inhibitors with a Seaweed Compound Diphenylmethane-Scaffold against Drug-Resistant Escherichia coli.

Drug-resistant efflux pumps play a crucial role in bacterial antibiotic resistance. In this study, potential efflux pump inhibitors (EPIs) with a diphenylmethane scaffold were screened and evaluated against drug-resistant Escherichia coli. Twenty-four compounds were docked against the drug-binding site of E. coli multidrug transporter AcrB, and 2,2-diphenylethanol (DPE), di-p-tolyl-methanol (DPT), and 4-(benzylphenyl) acetonitrile (BPA) were screened for their highest binding free energy. The modulation assay was further used for EPI evaluation, revealing that DPE, DPT, and BPA could reduce the drug IC50 value in E. coli strains overexpressing AcrB, indicating their modulation activity. Only DPE and BPA enhanced intracellular dye accumulation and inhibited the efflux of ethidium bromide and erythromycin. In addition, DPE and BPA showed an elevated post-antibiotic effect on drug-resistant E. coli, and they did not damage the permeability of the bacterial outer membrane. The cell toxicity test showed that DPE and BPA had limited human-cell toxicity. Therefore, DPE and BPA demonstrate efflux pump inhibitory activity, and they should be further explored as potential enhancers to improve the effectiveness of existing antibiotics against drug-resistant E. coli.

In silico studies of Ruellia tuberosa L. compounds as aldose reductase, dipeptidyl peptidase 4, and α-glucosidase inhibitors against type 2 diabetes mellitus

Context: The search for a safe and effective anti-diabetic medication has escalated due to the unfavorable side effects of synthetic drugs and the geometric rise in diabetes mellitus cases. Ruellia tuberosa is an important medicinal plant that can potentially reduce postprandial hyperglycemia. Aims: To identify the inhibition of aldose reductase, dipeptidyl peptidase 4 (DPP-4), and α-glucosidase for anti-diabetic drug discovery from Ruellia tuberosa bioactive compounds using computational methods, including molecular docking, binding free energy estimates and ADMET predictions. Methods: A molecular docking study of betulin, betulinic acid, cirsiliol, cirsimarin, cirsimaritin, and pedalitin with aldose reductase, DPP-4, and α-glucosidase inhibitors was done using Glide XP-docking module. The adsorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was carried out by the QikProp module, and ligand binding energy was ascertained by the prime molecular mechanics with generalized born and surface area (MM/GBSA) module, Schrodinger suite 2020-2. Results: The molecular docking and complexes' MM/GBSA show specific interactions and high binding free energies. The ADMET prediction demonstrates the excellent safety profile, pharmacokinetic characteristics, and favorable drug-likeness of betulin, betulinic acid, cirsiliol, cirsimarin, cirsimaritin, and pedalitin. This study shows the inhibition potential of Ruellia tuberosa compounds against aldose reductase, DPP-4, and α-glucosidase inhibitors. Conclusions: Therefore, for this chemical to be developed further into novel pharmaceuticals for treating type 2 diabetes mellitus, optimization and experimental research are required.

Discovery of putative inhibitors of human Pkd1 enzyme: Molecular docking, dynamics and simulation, QSAR, and MM/GBSA

Polycystic kidney disease is the most prevalent hereditary kidney disease globally and is mainly linked to the overexpression of a gene called PKD1. To date, there is no effective treatment available for polycystic kidney disease, and the practicing treatments only provide symptomatic relief. Discovery of the compounds targeting the PKD1 gene by inhibiting its expression under the disease condition could be crucial for effective drug development. In this study, a molecular docking and molecular dynamic simulation, QSAR, and MM/GBSA-based approaches were used to determine the putative inhibitors of the Pkd1 enzyme from a library of 1379 compounds. Initially, fourteen compounds were selected based on their binding affinities with the Pkd1 enzyme using MOE and AutoDock tools. The selected drugs were further investigated to explore their properties as drug candidates and the stability of their complex formation with the Pkd1 enzyme. Based on the physicochemical and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties, and toxicity profiling, two compounds including olsalazine and diosmetin were selected for the downstream analysis as they demonstrated the best drug-likeness properties and highest binding affinity with Pkd1 in the docking experiment. Molecular dynamic simulation using Gromacs further confirmed the stability of olsalazine and diosmetin complexes with Pkd1 and establishing interaction through strong bonding with specific residues of protein. High biological activity and binding free energies of two complexes calculated using 3D QSAR and Schrodinger module, respectively further validated our results. Therefore, the molecular docking and dynamics simulation-based in-silico approach used in this study revealed olsalazine and diosmetin as potential drug candidates to combat polycystic kidney disease by targeting Pkd1 enzyme.

Computer-aided prediction and molecular mechanism investigation of active components in compound Kushen injection inhibiting p21-activated kinase 1

Targeting p21-activated kinase 1 (PAK1) is a novel strategy for pancreatic cancer treatment. Compound Kushen injection contains many anti-pancreatic cancer components, but the specific targets are unknown. In this study, 14α-hydroxymatrine, an active component of Kushen injection, was found to possess high binding free energy with the allosteric site of PAK1 by molecular docking based virtual screening. Molecular dynamics simulations suggested that 14α-hydroxymatrine caused the α1 and α2 helices of the allosteric site of PAK1 to extend outward to form a deep allosteric regulatory pocket. Meanwhile, 14α-hydroxymatrine induced the β-folding region at the adenosine triphosphate (ATP)-binding pocket of PAK1 to close inward, resulting in the ATP-binding pocket in a "semi-closed" state which caused the inactivation of PAK1. After removal of 14α-hydroxymatrine, PAK1 showed a tendency to change from the inactive conformation to the active conformation. We supposed that 14α-hydroxymatrine of compound Kushen injection might be a reversible allosteric inhibitor of PAK1. This study used modern technologies and methods to study the active components of traditional Chinese medicine, which laid a foundation for the development and utilization of natural products and the search for new treatments for pancreatic cancer.

Secondary metabolic profiling, antioxidant potential, enzyme inhibitory activities and in silico and ADME studies: a multifunctional approach to reveal medicinal and industrial potential of Tanacetum falconeri

Tanacetum falconeri is a significant flowering plant that possesses cytotoxic, insecticidal, antibacterial, and phytotoxic properties. Its chemodiversity and bioactivities, however, have not been thoroughly investigated. In this work, several extracts from various parts of T. falconeri were assessed for their chemical profile, antioxidant activity, and potential for enzyme inhibition. The total phenolic contents of T. falconeri varied from 40.28 ± 0.47 mg GAE/g to 11.92 ± 0.22 mg GAE/g in various extracts, while flavonoid contents were found highest in TFFM (36.79 ± 0.36 mg QE/g extract) and lowest (11.08 ± 0.22 mg QE/g extract) in TFSC (chloroform extract of stem) in similar pattern as found in total phenolic contents. Highest DPPH inhibition was observed for TFFC (49.58 ± 0.11 mg TE/g extract) and TFSM (46.33 ± 0.10 mg TE/g extract), whereas, TFSM was also potentially active against (98.95 ± 0.57 mg TE/g) ABTS radical. In addition, TFSM was also most active in metal reducing assays: CUPRAC (151.76 ± 1.59 mg TE/g extract) and FRAP (101.30 ± 0.32 mg TE/g extract). In phosphomolybdenum assay, the highest activity was found for TFFE (1.71 ± 0.03 mg TE/g extract), TFSM (1.64 ± 0.035 mg TE/g extract), TFSH (1.60 ± 0.033 mg TE/g extract) and TFFH (1.58 ± 0.08 mg TE/g extract), while highest metal chelating activity was recorded for TFSH (25.93 ± 0.79 mg EDTAE/g extract), TFSE (22.90 ± 1.12 mg EDTAE/g extract) and TFSC (19.31 ± 0.50 mg EDTAE/g extract). In biological screening, all extracts had stronger inhibitory capacity against AChE while in case of BChE the chloroform extract of flower (TFFC) and stem (TFSC) showed the highest activities with inhibitory values of 2.57 ± 0.24 and 2.10 ± 0.18 respectively. Similarly, TFFC and TFSC had stronger inhibitory capacity (1.09 ± 0.015 and 1.08 ± 0.002 mmol ACAE/g extract) against α-Amylase and (0.50 ± 0.02 and 0.55 ± 0.02 mmol ACAE/g extract) α-Glucosidase. UHPLC-MS study of methanolic extract revealed the presence of 133 components including sterols, triterpenes, flavonoids, alkaloids, and coumarins. The total phenolic contents were substantially linked with all antioxidant assays in multivariate analysis. These findings were validated by docking investigations, which revealed that the selected compounds exhibited high binding free energy with the enzymes tested. Finally, it was found that T. falconeri is a viable industrial crop with potential use in the production of functional goods and nutraceuticals.

The Recognition Pathway of the SARS-CoV-2 Spike Receptor-Binding Domain to Human Angiotensin-Converting Enzyme 2.

COVID-19 caused by SARS-CoV-2 has spread around the world. The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 is a critical component that directly interacts with host ACE2. Here, we simulate the ACE2 recognition processes of RBD of the WT, Delta, and OmicronBA.2 variants using our recently developed supervised Gaussian accelerated molecular dynamics (Su-GaMD) approach. We show that RBD recognizes ACE2 through three contact regions (regions I, II, and III), which aligns well with the anchor-locker mechanism. The higher binding free energy in State d of the RBDOmicronBA.2-ACE2 system correlates well with the increased infectivity of OmicronBA.2 in comparison with other variants. For RBDDelta, the T478K mutation affects the first step of recognition, while the L452R mutation, through its nearby Y449, affects the RBDDelta-ACE2 binding in the last step of recognition. For RBDOmicronBA.2, the E484A mutation affects the first step of recognition, the Q493R, N501Y, and Y505H mutations affect the binding free energy in the last step of recognition, mutations in the contact regions affect the recognition directly, and other mutations indirectly affect recognition through dynamic correlations with the contact regions. These results provide theoretical insights for RBD-ACE2 recognition and may facilitate drug design against SARS-CoV-2.

Exploring the Potential Mechanisms of Guanxinshutong Capsules in Treating Pathological Cardiac Hypertrophy based on Network Pharmacology, Computer-Aided Drug Design, and Animal Experiments.

Cardiovascular diseases (CVDs) are significant causes of morbidity and mortality worldwide, and pathological cardiac hypertrophy (PCH) is an essential predictor of many heart diseases. Guanxinshutong capsule (GXST) is a Chinese patent medicine widely used in the clinical treatment of CVD, In our previous research, we identified 111 compounds of GXST. In order to reveal the potential molecular mechanisms by which GXST treats PCH, this study employed network pharmacology methods to screen for the active ingredients of GXST in treating PCH and predicted the potential targets. The results identified 26 active ingredients of GXST and 110 potential targets for PCH. Through a protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we confirmed AKT1, MAPK1, and MAPK3 as the core proteins in GXST treatment of PCH, thus establishing the PI3K/AKT and MAPK signaling pathways as the significant mechanisms of GXST in treating PCH. The results of molecular docking (MD) demonstrate that flavonoid naringenin and diterpenoid tanshinone iia have the highest binding affinity with the core protein. Before performing molecular dynamics simulations (MDSs), the geometric structure of naringenin and tanshinone iia was optimized using density functional theory (DFT) at the B97-3c level, and RESP2 atomic charge calculations were carried out at the B3LYP-D3(BJ)/def2-TZVP level. Further MDS results demonstrated that in the human body environment, the complex of naringenin and tanshinone iii with core proteins exhibited high stability, flexibility, and low binding free energy. Additionally, naringenin and tanshinone iia showed favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics and passed the drug similarity (DS) assessment. Ultrasound cardiograms and cardiac morphometric measurements in animal experiments demonstrate that GXST can improve the PCH induced by isoproterenol (ISO). Protein immunoblotting results indicate that GXST increases the expression of P-eNOS and eNOS by activating the PI3K/AKT signaling pathway and the MAPK signaling pathway, further elucidating the mechanism of action of GXST in treating PCH. This study contributes to the elucidation of the key ingredients and molecular mechanisms of GXST in treating PCH.

Biophysical and structural characterization of tetramethrin serum protein complex and its toxicological implications.

Tetramethrin (TMT) is a commonly used insecticide and has a carcinogenic and neurodegenerative effect on humans. The binding mechanism and toxicological implications of TMT to human serum albumin (HSA) were examined in this study employing a combination of biophysical and computational methods indicating moderate binding affinity and potential hepato and renal toxicity. Fluorescence quenching experiments showed that TMT binds to HSA with a moderate affinity, and the binding process was spontaneous and predominantly enthalpy-driven. Circular dichroism spectroscopy revealed that TMT binding did not induce any significant conformational changes in HSA, resulting in no changes in its alpha-helix content. The binding site and modalities of TMT interactions with HSA as computed by molecular docking and molecular dynamics simulations revealed that it binds to Sudlow site II of HSA via hydrophobic interactions through its dimethylcyclopropane carboxylate methyl propanyl group. The structural dynamics of TMT induce proper fit into the binding site creating increased and stabilizing interactions. Additionally, molecular mechanics-Poisson Boltzmann surface area calculations also indicated that non-polar and van der Waals were found to be the major contributors to the high binding free energy of the complex. Quantum mechanics (QM) revealed the conformational energies of the binding confirmation and the degree of deviation from the global minimum energy conformation of TMT. The results of this study provide a comprehensive understanding of the binding mechanism of TMT with HSA, which is important for evaluating the toxicity of this insecticide in humans.

Binding modes of a flexible ruthenium polypyridyl complex to DNA.

Ruthenium(II) polypyridyl complexes are attractive binders to DNA. Modifying the hydrophobicity, shape, or size of the ancillary ligands around the central ruthenium atom can induce changes in the binding mode to the DNA double helix. In this paper, we investigate the binding modes of [Ru(2,2'-bipyridine)2 (5-{4-[(pyren-1-yl)methyl]-1H-1,2,3-triazol-4-yl}-1,10-phenanthroline)]2+ (RuPy for short), a metal complex featuring a flexible pyrene moiety known for its intercalative properties. Classical molecular dynamics simulations are employed to gain insight into the non-covalent binding interactions of RuPy with two different 20 base pair DNA sequences, poly(dA)poly(dT) (AT) and poly(dC)poly(dG) (CG). In addition to examining the intercalation of the pyrene moiety from the major groove, the stability of RuPy-DNA adducts is investigated when the metal complex interacts externally with the DNA and with the major and minor groove pockets. The results indicate that external interaction and major groove binding are not stable, whereas intercalation consistently forms stable adducts. Minor groove binding showed less stability than intercalation and more variability, with some trajectories transitioning to intercalation, involving either the pyrene moiety or a bipyridine ligand. Pyrene intercalation, especially from the minor groove, was the most stable, while bipyridine intercalation was less favorable and associated with higher binding free energies.

Phytochemicals as potential inhibitors of interleukin-8 for anticancer therapy: in silico evaluation and molecular dynamics analysis

Within the realm of soluble factors that have emerged as potential targets for therapeutic intervention, the chemokine interleukin-8 (IL-8) has garnered attention as a potential contributor to treatment responses in various cancer types. The utilization of naturally occurring anticancer compounds for treating cancer patients has shown substantial advancements in survival rates across early and advanced stages of the disease. In silico research findings provide support for the application of phytochemicals as potential inhibitors of IL-8, and phytochemicals exhibiting a high binding free energy and crucial interactions display promising anticancer properties, positioning them as candidates for future drug development. Noteworthy phytochemicals such as IMPHY006634 (Isohydnocarpin), IMPHY007957 (Chitranone) and IMPHY013015 (1-Hydroxyrutaecarpine) were predicted to possess inhibitory activity against IL-8, with calculated energies ranging from −9.9 to −9.1 kcal/mol, respectively. Several hydrogen bonds, including common amino acid residues Lys9 and CYS48, were identified. Molecular dynamics calculations conducted on these potent inhibitors demonstrated their stability throughout a 200 ns simulation, as indicated by metrics such as RMSD, RMSF, Rg, SASA, H-bonds, PCA and FEL analysis. Moreover, PASS analysis and adherence of these natural compounds to drug-likeness rules like Lipinski’s further strengthen their candidacy. Considering these calculations and various parameters, these three prominent natural compounds emerge as promising candidates for anti-IL-8 therapy in the management of cancer. Communicated by Ramaswamy H. Sarma

Systems pharmacology-based dissection of potential mechanisms of Exocarpium Citri Grandis for the treatment of chronic bronchitis

Exocarpium Citri Grandis (ECG), a precious traditional Chinese medicine (TCM), has been widely utilized to improve the symptoms of chronic bronchitis (CB) such as cough or sputum. However, its underlying pharmacological mechanisms remain unclear. To investigate the potential mechanisms of ECG for the treatment of CB, a comprehensive systems pharmacology strategy combining network pharmacology, molecular docking, molecular dynamics simulations, and molecular biology experiments in vitro was carried out. In this study, 46 potential targets of CB screened for 10 active ingredients of ECG were strongly linked to inflammatory responses, immune processes, and apoptosis. Molecular docking revealed that the active ingredients of ECG have high binding activity for MyD88, NF-κB p65, Caspase9, and Caspase3, respectively. Meanwhile, MD simulations confirmed that neohesperidin and naringenin have high stability and low binding free energy with NF-κB p65 and Caspase3 in the binding pocket. In the LPS-induced RAW264.7 cell inflammatory model, ECG markedly reduced the secretion of IL1β, IL6, TNF-α, and NO. Transcriptomics showed a total of 337 differential expression genes (DEGs) were screened after ECG treatment, of which 233 down-regulated DEGs were closely associated with the NF-κ B signaling pathway, the Toll-like receptor signaling pathway, the IL-17 signaling pathway, and the TNF signaling pathway. Further analysis results revealed that ECG significantly down-regulated the expression of TLR4, MyD88, NF-κB p65, NF-κB p-p65 (S536), p-IκBα (S36), COX2, ICAM1, and iNOS, and up-regulated the expression of IκBα, inhibited NF-κB p65 entry into the nucleus, thereby suppressing NF-κB signaling transduction. Furthermore, ECG also significantly up-regulated the expression of Bcl-2 and down-regulated the expression of Bax, Caspase3, Caspase8, and Caspase9, inhibiting apoptosis in a dose-dependent manner. Our study reveals the potential pharmacological mechanisms of ECG for the treatment of CB and provides a scientific basis for its clinical application.

Exploring imidazo[4,5-g]quinoline-4,9-dione derivatives as Acinetobacter baumannii efflux pump inhibitor: an in silico approach

Antimicrobial resistance (AMR) is fast becoming a medical crisis affecting the entire global population. World Health Organization (WHO) statistics show that globally 0.7 million people are dying yearly due to the emergence of AMR. By 2050, the expected number of lives lost will be 10 million per year. Acinetobacter baumannii is a dreadful nosocomial pathogen that has developed multidrug resistance (MDR) to several currently prescribed antibiotics worldwide. Overexpression of drug efflux transporters (DETs) is one of the mechanisms of multidrug resistance (MDR) in Acinetobacter baumannii. Therefore, blocking the DET can raise the efficacy of the existing antibiotics by increasing their residence time inside the bacteria. In silico screening of five synthetic compounds against three drug efflux pump from A. baumannii has identified KSA5, a novel imidazo[4,5-g]quinoline-4,9-dione derivative, to block the efflux of antibiotics. Molecular docking and simulation results showed that KSA5 could bind to adeB, adeG, and adeJ by consistently interacting with ligand-binding site residues. KSA5 has a higher binding free energy and a lower HOMO-LUMO energy gap than PAβN, suggesting a better ability to interact and inhibit DETs. Further analysis showed that KSA5 is a drug-like molecule with optimal physicochemical and ADME properties. Hence, KSA5 could be combined with antibiotics to overcome antimicrobial resistance. Communicated by Ramaswamy H. Sarma