Docking Approach Research Articles

An Integrated Approach of Network Pharmacology, Bioinformatics, Molecular Docking, and Experimental Verification Uncovers Prunellae Spica as the potential Medicine of Prognosis Improvement for Oral Squamous Cell Carcinoma.

Prunellae Spica (PS), the spike from Prunella vulgaris L., is a traditional Chinese medicine that can treat Oral Squamous Cell Carcinoma (OSCC), whereas its molecular mechanisms and effects on the prognosis of patients remain unclear. Our study aimed to identify potential anti-OSCC targets of PS and explore its mechanisms and effects on prognosis through network pharmacology, bioinformatics analysis, molecular docking, and in vitro cell assays. Sixty-two potential targets of 11 active anti-OSCC ingredients of PS were identified, with Quercetin, the core ingredient of PS, exhibiting the most significant number of OSCC-related targets. GO analysis indicated that the primary biological processes involved in OSCC treatment by PS were the cellular response to nitrogen compound, response to xenobiotic stimulus, and cellular response to organonitrogen compound. KEGG analysis revealed that Pathways in cancer were the top highly enriched signaling pathway in the treatment of OSCC by PS. DisGeNET analysis is mainly about Lip and Oral Cavity Carcinoma. More importantly, 6 of the 62 targets were markedly related to prognosis. Molecular docking revealed high affinities between the key component and the prognosis-related target proteins. Treatment of OSCC cell line SCC-25 with Quercetin could inhibit malignant biological behaviors, such as cell proliferation, colony formation, invasion, and migration, as well as affect the targets related to prognosis and promote autophagy. Overall, these results suggest that PS plays a significant role in treating and improving the prognosis of OSCC by directly influencing various processes in OSCC.

The identification of potent dual-target monopolar spindle 1 (MPS1) and histone deacetylase 8 (HDAC8) inhibitors through pharmacophore modeling, molecular docking, molecular dynamics simulations, and biological evaluation.

Overexpression of monopolar spindle 1 (MPS1) and histone deacetylase 8 (HDAC8) is associated with the proliferation of liver cancer cells, so simultaneous inhibition of both MPS1 and HDAC8 could offer a promising therapeutic approach for the treatment of liver cancer. Dual-targeted MPS1/HDAC8 inhibitors have not been reported. A combined approach of pharmacophore modeling and molecular docking was used to identify potent dual-target inhibitors of MPS1 and HDAC8. Enzyme inhibition assays were performed to evaluate the optimal compound with the strongest inhibitory activity against MPS1 and HDAC8. The selectivity of MPH-5 for MPS1 and HDAC8 was assessed on a panel of 68 kinases and other histone deacetylases. Subsequently, molecular dynamics (MD) simulation verified the binding stability of the optimal compound to MPS1 and HDAC8. Ultimately, in vitro cellular assays and in vivo antitumor assays evaluated the antitumor efficacy of the most promising compound for the treatment of hepatocellular carcinoma. Six dual-target compounds (MPHs 1-6) of both MPS1 and HDAC8 were identified from the database using a combined virtual screening protocol. Notably, MPH-5 showed nanomolar inhibitory effect on both MPS1 (IC50 = 4.52 ± 0.21nM) and HDAC8 (IC50 = 6.07 ± 0.37nM). MD simulation indicated that MPH-5 stably binds to both MPS1 and HDAC8. Importantly, cellular assays revealed that MPH-5 exhibited significant antiproliferative activity against human liver cancer cells, especially HepG2 cells. Moreover, MPH-5 exhibited low toxicity and high efficacy against tumor cells, and it overcomes drug resistance to some extent. In addition, MPH-5 may exert its antitumor effects by downregulating MPS1-driven phosphorylation of histone H3 and upregulating HDAC8-mediated K62 acetylation of PKM2. Furthermore, MPH-5 showed potent inhibition of HepG2 xenograft tumor growth in mice with no apparent toxicity and presented favorable pharmacokinetics. The study suggests that MPH-5 is a potent, selective, high-efficacy, and low-toxicity antitumor candidate for the treatment of hepatocellular carcinoma.

Naturally Occurring Plant-Based Anticancerous Candidates as Potential ERK2 Inhibitors: In-Silico Database Mining and Molecular Dynamics Simulations.

The evolutionarily conserved extracellular signal-regulated kinase 2 (ERK2) is involved in regulating cellular signaling in both normal and pathological conditions. ERK2 expression is critical for human development, while hyperactivation is a major factor in tumor progression. Up to now, there have been no approved inhibitors that target ERK2, and as such, here we report on screening of a naturally occurring plant-based anticancerous compound-activity-target (NPACT) database for prospective ERK2 inhibitors. More than 1,500 phytochemicals were screened using in-silico molecular docking and molecular dynamics (MD) approaches. NPACT compounds with a docking score lower than a co-crystallized LHZ inhibitor (calc. -10.5 kcal/mol) were subjected to MD simulations. Binding energies (ΔGbinding) of inhibitor-ERK2 complexes over the MD course were estimated using an MM-GBSA approach. Based on MM-GBSA//100 ns MD simulations, the steroid zhankuic acid C (NPACT01034) demonstrated greater binding affinity against ERK2 protein than LHZ, with ΔGbinding values of -50.0 and -47.7 kcal/mol, respectively. Structural and energetical analyses throughout the MD course demonstrated stabilization of zhankuic acid C complexed with ERK2 protein. The anticipated ADMET properties of zhankuic acid C indicated minimal toxicity. Moreover, in-silico evaluation of fourteen ERK2 inhibitors in clinical trials demonstrated the higher binding affinity of zhankuic acid C towards ERK2 protein.

Network pharmacology and molecular docking approach to elucidate the mechanisms of safflower, phellodendron, scutellaria baicalensis, coptis, and gardenia in hand-foot syndrome.

Safflower, phellodendron, scutellaria baicalensis, coptis, and gardenia (SPSCG) are medicinal plants with a wide range of anti-inflammatory and antioxidant effects. However, the related mechanism of SPSCG against hand-foot syndrome (HFS) has yet to be revealed. To investigate the mechanisms of SPSCG in the treatment of HFS using the Network Pharmacology. Active ingredients and targets of SPSCG for HFS were screened by the Chinese Medicine Systems Pharmacology (TCMSP) and Swiss Target Prediction databases. Potential therapeutic targets were collected from the GeneCards and OMIM databases. Subsequently, protein-protein interactions (PPI), Gene Ontology (GO) annotations, and pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to investigate the potential mechanism of the SPSCG in HFS. Then, molecular docking and molecular dynamics simulations were performed to predict the binding interactions between the active compound and the core target. Finally, vitro experiments were used to verify the repair effect of key ingredients of SPSCG on cell damage caused by 5-Fluorouracil. Quercetin, kaempferol, β-sitosterol, and stigmasterol were identified as the major active components of SPSCG. GO analysis showed a total of 1,127 biological processes, 42 terms cellular components, and 57 molecular functions. KEGG analysis showed that the MAPK, TNF, and IL-17 signaling pathways were significantly enriched. The PPI analysis discovered that EGFR, CASP3, AKT1, CCND1, and CTNNB1 shared the highest centrality among all target genes. The experimental results confirmed that these SPSCG active ingredients could treat HFS by reducing inflammation reaction and promoting cell damage repair. SPSCG may alleviate HFS by exerting antioxidative effects and suppressing inflammatory responses.

Uncovering naringin’s anticancer mechanisms in glioblastoma via molecular docking and network pharmacology approaches

Naringin, a flavonoid, exhibits diverse therapeutic properties and has been proven to exert cytotoxic effects on cancer cells. Nevertheless, the precise mechanism of naringin maintaining its cytotoxic effect on glioblastoma (GBM) remains unknown. Thus, the current study aimed to establish a plausible cellular mechanism for Naringin’s inhibition of GBM. We employed various system biology techniques to forecast the primary targets, including gene ontology and cluster analysis, KEGG enrichment pathway estimation, molecular docking, MD (molecular dynamic) simulation and MMPBSA analysis. Glioblastoma target sequences were obtained via DisGeNet and Therapeutic Target Prediction, aligned with naringin targets, and analyzed for gene enrichment and ontology. Gene enrichment analysis identified the top ten hub genes. Further, molecular docking was conducted on all identified targets. For molecular dynamics modelling, we selected the two complexes that exhibited the most docking affinity and the two most prominent genes of the hub identified through analysis of the enrichment of genes. The PARP1 and ALB1 signalling pathways were found to be the main regulated routes. Naringin exhibited the highest binding potential of − 12.90 kcal/mol with PARP1 (4ZZZ), followed by ABL1 (2ABL), with naringin showing a − 8.4 kcal/mol binding score, as determined by molecular docking. The molecular dynamic approach and MM-PBSA investigation along with PCA study revealed that the complex of Naringin, with 4ZZZ (PARP1) and, 2ABL (ABL1), are highly stable compared to that of imatinib and talazoparib. Analyses of the signalling pathway suggested that naringin may have anticancer effects against GBM by influencing the protein PARP and ALB1 levels. Cytotoxicity assay was performed on two different glioblastoma cell lines C6 and U87MG cells. Naringin demonstrates a higher cytotoxic potency against U87MG human glioblastoma cells compared to C6 rat glioma cells.

Characterization of natural compounds derived from diatom C. gracilis as potential therapeutic agents: An in-silico networking and docking study

Marine diatom Chaetoceros gracilis have been known as the key player regulating the nutritional content of aquaculture species. Being able to synthesize an array of high value bioactive compounds like amino acids, lipids, terpenoids and polysaccharides, it also serves as potential therapeutic and nutraceutical agent. This in silico-based study elucidates the interactive association of different compounds, proteins and pathways of the diatom C. gracilis through an integrated network pharmacology and molecular docking approach. According to the Network analysis of the 41 compounds detected, saturated hydrocarbons, diterpenoids and phenolic compounds scored the highest degree (score > 140). These compounds were further coded for approximately 349 protein targets and almost 490 different pathways. HSP90AA1, STAT3, HIF1A, MTOR, ESR1, PIK3CA, MAPK1 and PTGS2 secured highest degree of protein-protein interaction according to STRING database. The gene enrichment analysis further revealed that these proteins were closely associated with metabolic pathways like Pathways in cancer, neuroactive ligand-receptor interaction, calcium and cAMP signaling pathway, PI3K-Akt signaling pathway, Alzheimer's disease and pathways of neurodegeneration which played an instrumental role in the metabolism of diseases and disorders like cancers of breast, prostrate, and liver, schizophrenia and other mental and hypertensive disorders. Furthermore, the molecular docking and toxicity assessment of a few novel compounds was done with mTOR and HSP90AA1 which revealed promising and stable interactions. Thus, this study provides the first in silico insight outlining the anti-cancerous and neuroprotective potential of novel bioactive compounds derived from marine diatom C.gracilis.

Designing of some VO(II), Co(II) and Hg(II) Schiff base complexes: Synthesis, structure elucidation, anticancer and biopesticidal activities, DFT and docking approaches

New VO(II), Co(II) and Hg(II) chelates of bi- or tetradentate isatin based ligand i.e.:-2-(((E)-2-oxo-1,4-dihydrocyclohepta [b]pyrrol-3(2H)-ylidene)amino)-N-(8-((1-(2-((E)-2-oxoindolin-3-phenyl)vinyl) amino) naphthalen-1-yl) benzamide (H2L) were synthesized and well characterized. The reaction between N,N′-(naphthalene-1,8-diyl)bis(2-aminobenzamide) and di-oxazine-2,4 dione (isatin) yielded the Schiff base (H2L). The compounds have been identified by different physicochemical and spectroscopic approaches and DFT as well. From all measurements square pyramidal, distorted octahedral or square planar configurations have been suggested for the chelates 1, 2 and 3, respectively. The Coats-Redfern equations were used to calculate and define the dynamics properties of decomposition stages from TGA (Ea, A, ΔH*, ΔS*, and ΔG*). The in vitro anticancer property of the obtained compounds towards human hepato (HepG2) and human breast (MCF-7) carcinoma cell lines has been screened. Also, the biopesticidal effect of these compounds against spodoptera littoralis has been examined. Data showed that, the tested [Hg(H2L)(L)] complex (3) possesses the most anticancer efficacy against both HepG2 and MCF-7 cells, with half inhibitory concentration (IC50) = 5.78 ± 0.029, 11.24 ± 0.58 μg/mL, respectively also, this complex considered as good an insecticide with the concentration lethal to 50 percent of test organisms (LC50) = 27585.45 ppm after 72 h. The insecticide and tumor inhibition properties were compared with the theoretical molecular docking findings with the specification of the active species in the designated proteins.

Sourcing antimicrobial agents from Globimetula braunii: An in silico molecular docking and dynamic approach

The continued emergence of multi-drug resistance pathogens has been a major setback to lifting the burden of infectious diseases, especially bacterial illnesses. Natural- and/or nature-inspired compounds have so far become a therapeutic backbone on which many novel antibacterial agents are optimized. It is against this backdrop that we used an in silico molecular interaction-based approach to screen five previously identified compounds from Globimetula braunii, for lead inhibitors against bacterial illnesses. The compounds were chromatographed from the leaf ethyl acetate fraction and were characterized by spectroscopic means as 13,27-cycloursane (1), 13,27-cycloursan-3-one (2), methyl-3,5-dihydroxy-4-methoxybenzoate (3), 3-methyl-4-hydroxybenzoate (4), and 2-methoxyphenol (5). Upon their molecular docking at the active pocket of the Staphylococcus aureus gyrase B and the Escherichia coli DNA gyrase, 2 showed the highest binding affinities, with energy scores of -10 and -9.6 Kcal/mol. These were better than the standard antibiotics, Ampicillin (-7.5 and -8.0 Kcal/mol), and Ciprofloxacin (-6.9, -8.4 Kcal/mol). Further evaluation of the most promising compound 2 by molecular dynamics simulation showed the mean RMSD values of the 13,27-cycloursan-3-one - E. coli DNA gyrase protein complexes (complex 1) and 13,27-cycloursan-3-one - S. aureus gyrase B protein (complex 2) to be 0.7 and 0.9 Ǻ respectively, attaining stability at 102 and 108 ns. In contrast, complexes 1 and 2’s RMSF analysis revealed the fewest fluctuations and was generally stable over the course of the 120 ns. In conclusion, 13,27-cycloursan-3-one is unquestionably the most promising inhibitory candidate against the bacterial growth protein DNA gyrase, hence, it can be considered as a druggable substance against bacterial disease.

Pharmacophore-Based Study: An In Silico Perspective for the Identification of Potential New Delhi Metallo-β-lactamase-1 (NDM-1) Inhibitors.

In the ongoing battle against antibiotic-resistant bacteria, New Delhi metallo-β-lactamase-1 (NDM-1) has emerged as a significant therapeutic challenge due to its ability to confer resistance to a broad range of β-lactam antibiotics. This study presents a pharmacophore-based virtual screening, docking, and molecular dynamics simulation approach for the identification of potential inhibitors targeting NDM-1, a critical enzyme associated with antibiotic resistance. Through the generation of a pharmacophore model and subsequent virtual screening of compound libraries, candidate molecules (ZINC29142850 (Z1), ZINC78607001 (Z2), and ZINC94303138 (Z3)) were prioritized based on their similarity to known NDM-1 binder (hydrolyzed oxacillin (0WO)). Molecular docking studies further elucidated the binding modes and affinities of the selected compounds towards the active site of NDM-1. These compounds demonstrated superior binding affinities to the enzyme compared to a control compound (-7.30 kcal/mol), with binding scores of -7.13, -7.92, and -8.10 kcal/mol, respectively. Binding interactions within NDM-1's active site showed significant interactions with critical residues such as His250, Asn220, and Trp93 for these compounds. Subsequent molecular dynamics simulations were conducted to assess the stability of the ligand-enzyme complexes, showing low root mean square deviation (RMSD) values between 0.5 and 0.7 nm for Z1, Z2, which indicate high stability. Z2's compactness in principal component analysis (PCA) suggests that it can stabilize particular protein conformations more efficiently. Z2 displays a very cohesive landscape with a notable deep basin, suggesting a very persistent conformational state induced by the ligand, indicating robust binding and perhaps efficient inhibition. Z2 demonstrates the highest binding affinity among the examined compounds with a binding free energy of -25.68 kcal/mol, suggesting that it could offer effective inhibition of NDM-1. This study highlights the efficacy of computational tools in identifying novel antimicrobial agents against resistant bacteria, accelerating drug discovery processes.

Rational design of a multi-epitope vaccine against heartland virus (HRTV) using immune-informatics, molecular docking and dynamics approaches

Heartland virus (HRTV) is a single-stranded negative-sense RNA virus that infects human beings. Because there are no antiviral medications available to treat HRTV infection, supportive care management is used in cases of severe disease. Therefore, it has spurred research into developing a multi-epitope vaccine capable of providing effective protection against HRTV infection. A multi-epitope vaccine was created using a combination of immuno-informatics, molecular docking and molecular dynamics simulation in this investigation. The HRTV proteome was utilized to predict B-cell, T-cell (HTL and CTL), and IFN-epitopes. Following prediction, highly antigenic, non-allergenic and immunogenic epitopes were chosen, including 6 CTL, 8 HTL, and 5 LBL epitopes that were connected to the final peptide by AAY, GPGPG, and KK linkers, respectively. An adjuvant was introduced to the vaccine's N-terminal through the EAAAK linker to increase its immunogenicity. Following the inclusion of linkers and adjuvant, the final construct has 359 amino acids. The presence of B-cell and IFN-γ-epitopes validates the construct's acquired humoral and cell-mediated immune responses. To ensure the vaccine's safety and immunogenicity profile, its allergenicity, antigenicity, and various physicochemical characteristics were assessed. Docking was used to assess the binding affinity and molecular interaction between the vaccination and TLR-3. In silico cloning was used to confirm the construct's validity and expression efficiency. The results of these computer assays demonstrated that the designed vaccine is highly promising in terms of developing protective immunity against HRTV; nevertheless, additional in vivo and in vitro investigations are required to validate its true immune-protective efficiency.

Phytochemical profiles, bioactivities, and molecular docking and molecular dynamics approaches of endemic Campanula baskilensis Behçet (campanulaceae)

Campanula species have phenolic derivatives with a broad biological potential. This study aimed to investigate the chemical contents, bioactivities, and prediction of the biological effect mechanism using the molecular docking study for C. baskilensis (CB) leaf (L), root (R), and stem (S) extracts.CBL gave the highest phenolic contents as hesperidin at 7.56 mg/g extract. Total phenolic and flavonoid contents of CBS were determined as 3.12 ± 0.05 mg GAE/g and 1.11 ± 0.11 mg QE/g, respectively. CBS and CBL exhibited high DPPH• scavenging, H2O2 scavenging, AChE, BChE, carbonic anhydrase, lipase, and tyrosinase inhibition effects and demonstrated potent antimicrobial activity. The strong phenolic components of CBS and CBL extracts contributed to their biological activities. According to the molecular docking results, a high inhibition effect was observed on the inhibition activities due to the presence of hesperidin, which is the highest main component of the extracts. Additionally, docking studies were performed on hesperidin for the first time. Dynamics study showed that the interaction between the hesperidin and BChE increased stability, producing a stable complex form within 100 ns. In conclusion, C. baskilensis extracts, especially hesperidin, may be promising potential sources for neurological diseases and complementary medicine.

Insights into the mechanism of Danggui Liuhuang Tang in treating night sweats: A network pharmacology and molecular docking approach.

Night sweats can occur independently or in association with a number of medical conditions and can significantly disrupt daily life. This study focuses on the treatment of primary night sweats. Despite the considerable interest in Danggui Liuhuang Tang (DGLHT), an effective traditional Chinese medicine formula, its mechanism of action remains unknown. There is also no existing literature on the subject. Network pharmacology and molecular docking techniques. Network pharmacology techniques were employed to identify 109 active ingredients and 808 potential targets of DGLHT, as well as 2385 targets associated with night sweating diseases. The screening process yielded 375 common targets shared between DGLHT and night sweating. These included the active ingredients baicalein, quercetin, huarangiin, and tetrahydroafrican antipyrine, and the core targets interleukin 6, serine/threonine protein kinase 1, tumor necrosis factor, GAPDH enzyme, and Src protein kinase were identified. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that DGLHT exerts its therapeutic effects primarily by modulating the PI3K-Akt signaling pathway, neuroactive ligand-receptor interactions, lipid metabolism, and atherosclerosis pathways. Molecular docking revealed strong binding activity between the main active ingredients and their potential targets. The research identifies promising active ingredients and targets related to the effectiveness of DGLHT in controlling night sweats, thus contributing to the further exploration of potential therapeutics for this condition. In addition, the results of this experiment provide a basis for future research into night sweats.

In-silico evaluation of phytochemicals for vitiligo: ADMET, molecular docking, and MD simulation approaches

Vitiligo is a prevalent autoimmune disease affecting the quality of life and self-confidence. Total 25 phytochemicals from plants were screened by using four target proteins involved in the pathogenesis of vitiligo. The binding affinity of the ligands ranged between −10.3 and −4.5 kcal/mol. The top 10 phytochemicals i.e. rosmarinic acid, piperine, tamarixetin, desmethoxycurcumin, bisdemethoxycurcumin, isorhamnetin, quercetin, vicenin II, genkwanin, and aloe-emodin showed good inhibition with binding affinity ranged from −10.3 to 9.4 Kcal. The ADMET profiling revealed that these phytochemicals might be safe for the treatment of vitiligo. In MD simulation, rosmarinic acid, piperine, and tamarixetin with MAO-A formed stable complexes and the free binding energies of the complexes were −34.02 ± 6.94, −33.51 ± 2.65, and −27.17 ± 3.28. Furthermore, the ligands formed hydrogen bonds with targets, suggested that rosmarinic acid, piperine, and tamarixetin have potential to serve as lead compounds for developing novel therapeutics for vitiligo after in vitro and in vivo studies.

Evaluation of Co(II) Schiff base complexes: Catalysis, theoretical and biomolecular interaction studies

Two Schiff base ligands, namely H2L1 [3-(2‑hydroxy-phenylimino)-1,3-dihydro-indole-2-one] and H2L2 [3-(2-mercapto-phenylimino)-1,3-dihydro-indole-2–1], were successfully synthesized. Furthermore, the ligands were subsequently complexed with [CoCl2(PPh3)3] to form CoL1 and CoL2, respectively. The synthesized metal complexes were investigated using FTIR, UV–Visible, and NMR spectroscopic techniques. Catalytic efficiency was evaluated for the oxidation of alcohol and C6H5-H5C6Coupling reactions. DFT study verified the structural parameters of the prepared Co2+ complexes were made reliable. The interaction of Co2+ Schiff base complexes with BSA and DNA were studied using an in-silico docking approach.

Comparative bioengineering and optoelectronic properties of metoprolol by DFT, molecular docking, and molecular dynamic approaches

The biophysical properties of metoprolol are investigated by the full potential-linearized augmented plane wave method and molecular docking and molecular dynamic approaches. The exchange–correlation potentials are calculated by the Perdew–Burke–Ernzerhof generalized gradient approximation as implemented in the WIEN2k package. The electronic results show the insulator nature of metoprolol with the indirect bandgap of 3.74 eV between HOMO and LUMO states. In the density of state spectra, the p state of O, C, and N elements confirm the stability of metoprolol. Metoprolol exhibits a metallic behavior in the z direction, while it has a dielectric behavior in the x and y directions. The static refractive indices are obtained 1.49, 1.53, and 1.63 in the x, y, and z directions, respectively. It was found that the maximum reflectivity occurs at the ultraviolet region in the z-direction. The calculated absorption spectra also confirm the other’s experimental results. The obtained results of molecular docking indicate the formation of hydrogen bonds between metoprolol and the beta-2 adrenergic receptors, and molecular dynamics showed a human beta-2 adrenoceptor either in its free state or in complex with a metoprolol molecule. The calculated binding energies of elements by molecular docking and the other biological properties of metoprolol by molecular dynamic are in close agreement with obtained Density Functional Theory (DFT) results for Pharmacia applications.

Carbonic anhydrase 2 mediates anti-obesity effects of black tea as thermogenic activator

Obesity is a metabolic disorder due to over-accumulation of adipose tissue and ultimately becomes a “disease”. Brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning emerge as a potential strategy of anti-obesity by dissipating energy as heat. However, drugs based on adipose tissue thermogenesis have not been successfully approved yet. In current study, we found that black tea extract (BTE) obtained by patent-authorized manufacturing process prevented body weight gain as novel thermogenic activator with reduction of adiposity, improvement of adipose distribution, and glucose metabolism improvement in diet-induced obesity mice. Mechanismly, anti-obesity effect of BTE depends on promoting BAT thermogenesis and WAT browning with upregulation of uncoupling protein 1 (UCP1), especially visceral adipose tissue (VAT) with browning resistance. Specifically, utilizing in silico approach of network pharmacology and molecular docking, we identified carbonic anhydrase 2 (CA2) in nitrogen metabolism as anti-obesity target of BTE and further elucidated that protein kinase B (AKT) signaling pathway linked CA2 and UCP1. Meanwhile gut microbiota regulation may prompt the CA2-dependent thermogenesis activation. Our findings demonstrated anti-obesity effect of BTE as thermogenic activator through CA2-mediated BAT thermogenesis and WAT browning via CA2-AKT-UCP1 signaling pathway, which could be developed as promising anti-obesity agent with good safety and efficacy.

Molecular docking and molecular dynamics study of 3-hydroxybutyrate with polymers for diabetic ketoacidosis-targeted molecularly imprinted polymers

Context: Molecularly imprinted polymers (MIPs) are promising materials with tailored binding sites that can selectively recognize and bind target molecules. The combined approach of molecular docking and molecular dynamics (MD) simulation provides valuable insights into the interactions between 3-hydroxybutyrate (3HB) and the designed MIPs, shedding light on the intricate details of their binding mechanisms. This information is crucial for designing MIPs with high selectivity and affinity for 3HB, which is a key biomarker of diabetic ketoacidosis (DKA). Aims: To examine the interactions and dynamic behavior of 3HB in a complex with ten polymers by employing molecular docking and MD simulations. Methods: Initially, molecular docking was employed to predict the binding orientations and affinities of the 3HB molecule within the active sites of the polymers. Subsequently, molecular dynamics simulation was utilized to explore the dynamic behavior, stability, and interactions within these complexes for 100 ns. Metabolic and toxicological properties of 3HB using SwissADME were also predicted. Results: N-(hydroxymethyl)acrylamide (NHMAm), hydroxyethyl methacrylate (HEMA), itaconic acid (ITA), and N-[tris(hydroxymethyl)methyl]acrylamide (TrisNHMAm) displayed the strongest interactions with 3HB, with binding affinities of -2.64, 2.523, 2.469, and 2.305 kcal/mol, respectively. Various kinds of molecular interactions influence ligand-polymer binding in a variety of ways, as illustrated by the four polymers with the lowest binding affinities. In molecular dynamics, 4-vinylpyridine (4VP), N,N-dimethylacylamide (DMAm), N-(hydroxyethyl)acrylamide (NHEAm), and hydroxyethyl methacrylate (HEMA) suggest a strong stable complex with 3HB with an overall ΔTOTAL of -0.56, -0.35, -0.32, and -0.27 kcal/mol, respectively. The ADME prediction indicated that 3HB has favorable pharmacokinetic properties. Conclusions: HEMA shows the ability to interact well with 3HB both by molecular docking and molecular dynamics.

In Silico and In Vitro Investigation of Phytoconstituents from Flacourtia Jangomas as a Potential Candidate for the Treatment of Type 2 Diabetes Mellitus

AbstractFlacourtia jangomas is a plant used for centuries in Brazil, China, India, and the Malaya Peninsula to treat conditions such as diabetes, asthma, anaemia, and diarrhoea. Despite its therapeutic and economic benefits, the plant has not been popular among farmers due to its limited yield and lack of knowledge about its potential. Targeting PPARγ agonists is a promising approach for discovering and developing effective drugs to treat type 2 diabetes. Due to the activation of the PPARγ through PPARγ agonists, target genes implicated in inflammation, adipogenesis, lipid metabolism, and glucose metabolism are transcriptionally regulated. This study analysed the curated datasets of F. jangomas to identify the binding conformations of the phytoconstituents with different T2DM targets through molecular docking, molecular dynamics, and ADMET prediction approach. To determine the most favourable binding conformations of phytoconstituents that bind with the PPARγ receptors, density functional theory and principal component analysis were performed. The study reveals that the phytoconstituents of F. jangomas can act as PPARγ agonists and could be used to design and optimise the potential antidiabetic agents inspired by natural products. These findings provide a promising approach towards developing effective antidiabetic drugs.

Insights into bacterial interactions: Comparing fluorine-containing 1,2,4-triazoles to antibiotics using molecular docking and molecular dynamics approaches

Understanding the interactions between drugs and enzymes is crucial for designing effective therapeutics. This study employed a combination of molecular docking and molecular dynamics (MD) simulations to evaluate the binding affinity, stability, and dynamic behavior of two new compounds (compound 1 and compound 2) compared to vancomycin and meropenem against Staphylococcus aureus and Serratia marcescens bacterial enzymes. Molecular docking studies provided insights into the binding interactions and affinities of these compounds, revealing that both compound 1 and compound 2 exhibit promising binding profiles. In particular, compound 1 demonstrated lower binding energies with key enzymes from Staphylococcus aureus compared to vancomycin, suggesting enhanced potential. MD simulations further elucidated the dynamic stability of these complexes. Results indicated that compound 1 maintains consistent binding modes with low RMSD and RMSF values, implying stable interactions. In contrast, vancomycin exhibited high RMSD and RMSF values in some enzyme complexes, reflecting potential instability. Compound 2 showed competitive stability and binding behavior compared to meropenem, with comparable RMSD and RMSF values across various enzyme targets. These findings highlight the potential of compound 1 and compound 2 as viable candidates for further development, offering insights into their stability and efficacy as new therapeutic agents.

Exploration of Active Ingredients, Targets, and Potential Mechanisms of Er-Miao-San in the Treatment of Colorectal Cancer Based on Network Pharmacology and Molecular Docking Technology

Background Er-Miao-San (EMS) is a classic prescription in Traditional Chinese Medicine (TCM) for the treatment of colorectal cancer (CRC) and has shown promising therapeutic effects in clinical practice. However, the specific components and molecular mechanisms of EMS remain unclear. Purpose The aim of this study was to analyze the effective components and molecular mechanisms of EMS in treating CRC through network pharmacology techniques and experimental validation. Materials and Methods The Traditional Chinese Medicine Systems Pharmacology database was used to screen the main active chemical components and targets of the EMS formula. The compound structures were verified using the PubChem database, which is an organic small-molecule bioactivity database. GeneCards and OMIM databases were utilized to predict target genes related to CRC. The Cytoscape 3.8 software was used to construct a “Drug-Active Ingredient-Target-Disease” intersection network. The STRING database was employed to analyze the core target protein–protein interaction network shared by EMS and CRC. The core targets were further subjected to Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis using the R language. Molecular docking between the core targets and the major active chemical components of EMS was performed using AutoDock software. The impact of the core targets on the prognosis of CRC patients was analyzed using the R language. Subsequently, we validated the potential mechanisms predicted by network pharmacology for the inhibition of CRC cell proliferation by the key proteins in the relevant pathways through CCK8 cell proliferation assays and Western blot experiments. Results Molecular docking results showed good docking affinity between the key active components, such as quercetin and baicalein, of EMS and the core targets. Kaplan–Meier survival analysis demonstrated a close correlation between the core targets and the survival prognosis of CRC patients. Cellular experiments showed that EMS significantly inhibited the proliferation of CRC cells and may promote apoptosis and autophagy of CRC cells by suppressing the expression of key proteins in the PI3K/AKT pathway. Conclusion The TCM formula EMS exerts anti-CRC effects through multiple pathways and targets, improving the prognosis and extending the survival period of CRC patients. This study provides preliminary insights into the effective components and molecular mechanisms of EMS in the treatment of CRC, which were preliminarily validated through molecular docking and experimental approaches.