Molecular mechanisms, targets and clinical potential of berberine in regulating metabolism: a review focussing on databases and molecular docking studies.

Background: Metabolic imbalance is the common basis of many diseases. As natural isoquinoline alkaloid, berberine (BBR) has shown great promise in regulating glucose and lipids metabolism and treating metabolic disorders. However, the related mechanism still lacks systematic research. Aim: To discuss the role of BBR in the whole body's systemic metabolic regulation and further explore its therapeutic potential and targets. Method: Based on animal and cell experiments, the mechanism of BBR regulating systemic metabolic processes is reviewed. Potential metabolism-related targets were summarized using Therapeutic Target Database (TTD), DrugBank, GeneCards, and cutting-edge literature. Molecular modeling was applied to explore BBR binding to the potential targets. Results: BBR regulates the whole-body metabolic response including digestive, circulatory, immune, endocrine, and motor systems through adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), sirtuin (SIRT)1/forkhead box O (FOXO)1/sterol regulatory element-binding protein (SREBP)2, nuclear factor erythroid 2-related factor (Nrf) 2/heme oxygenase (HO)-1, and other signaling pathways. Through these reactions, BBR exerts hypoglycemic, lipid-regulating, anti-inflammatory, anti-oxidation, and immune regulation. Molecular docking results showed that BBR could regulate metabolism targeting FOXO3, Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase (Gpx) 4 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). Evaluating the target clinical effects, we found that BBR has the therapeutic potential of anti-aging, anti-cancer, relieving kidney disease, regulating the nervous system, and alleviating other chronic diseases. Conclusion: This review elucidates the interaction between potential targets and small molecular metabolites by exploring the mechanism of BBR regulating metabolism. That will help pharmacologists to identify new promising metabolites interacting with these targets.

Comprehensive study on pharmacognostic, pharmacological, and toxicological features of Ficus racemosa in Alzheimer's disease using GC-MS and molecular docking analyses.

Background: Alzheimer's disease (AD) presents as a widespread neurodegenerative condition impacting over 55 million individuals globally, with an annual rise of 10 million new cases. Despite its staggering prevalence, the absence of a definitive cure establishes the need for a revisit. Methods: We explore the alternative strategies, focusing on the potential therapeutic efficacy of ethanolic extracts derived from the fruit and leaf of Ficus racemosa Linn. Results: The investigation comprehensively explores pharmacognostic, phytochemical, toxicological, and pharmacological characteristics. In addition to pharmacognostic and physicochemical analyses, toxicological evaluations conducted on experimental animals demonstrated the innocuous nature of the ethanolic extracts (from both fruit and leaf) of F. racemosa, as evidenced by assessments of hemocompatibility, oxidative parameters, and vital organ histology. Phytochemical profiling via GC-MS identified 48 and 80 phytoconstituents in the fruit and leaf extracts, respectively. These constituents were screened for bioactive potential using the "Lipinski Rule of Five," resulting in the selection of 25 and 33 constituents from fruit and leaf extracts, respectively. Subsequent molecular docking studies against the AChE enzyme revealed promising interactions of the selected phytoconstituents. Furthermore, the top-scoring phytoconstituents were subjected to in silico screening to assess their interactions with ß- and γ-secretase enzymes, in addition to the AChE enzyme. The cumulative findings substantiate the therapeutic utility of the plant extracts, particularly in the context of AD. Conclusion: In conclusion, our investigation highlights the promising therapeutic potential of selected phytoconstituents derived from ethanolic extracts of F. racemosa in mitigating AD pathology by targeting key enzyme sites such as AChE, ß-, and γ-secretase.

Morroniside attenuates podocytes lipid deposition in diabetic nephropathy: A network pharmacology, molecular docking and experimental validation study.

BACKGROUND: Dysregulation of lipid metabolism is a key factor influencing the progression of diabetic nephropathy (DN). Morroniside (MOR) is a major active compound isolated from the traditional Chinese herb Cornus officinalis, our previous research found that it can improve the lipid deposition of renal tubular epithelial cells. The purpose of this study is to explore whether MOR can improve podocyte lipid deposition and its mechanism of reducing DN. METHODS: Initially, we used network pharmacology and bioinformatics techniques to predict the relationship between renal lipid metabolism of MOR and DN. Subsequently, the binding activity of MOR with lipid-related proteins was studied by molecular docking to determine how MOR acts through these proteins. After determining the target of MOR, animal experiments and cell tests were carried out to verify it. RESULTS: Using network pharmacology, bioinformatics, and molecular docking, target proteins for MOR treatment of DN were predicted and screened, including PGC-1α, LXRs, ABCA1, PPARY, CD36, and nephrin. It is particularly noted that MOR effectively binds to PGC-1α, while LXRs, ABCA1, PPARY and CD36 are downstream molecules of PGC-1α. Silencing the PGC-1α gene significantly reduced the therapeutic effects of MOR. Conversely, in groups without PGC-1α knockdown, MOR was able to increase the expression levels of PGC-1α and influence the expression of downstream proteins. Furthermore, through in vivo and in vitro experiments, utilizing techniques such as lipid droplet staining, PAS, MASSON staining, immunofluorescence, and Western blot, we found that MOR effectively elevated the expression levels of the podocyte protein nephrin and lipid metabolism-regulating proteins PGC-1α, PPARY, and ABCA1, while significantly inhibiting the expression of the lipid accumulation promoter CD36. CONCLUSION: MOR can regulate the cholesterol efflux in podocytes via the PGC-1α/LXRs/ABCA1 signaling pathway, and control cholesterol intake via the PGC-1α/PPARY/CD36 signaling pathway, thereby ameliorating lipid deposition in DN.

Synthesis, biological evaluation, theoretical calculations, QSAR and molecular docking studies of novel arylaminonaphthols as potent antioxidants and BChE inhibitors.

A completely green protocol was developed for the synthesis of a series of arylaminonaphthol derivatives in the presence of N-ethylethanolamine (NEEA) as a catalyst under ultrasonic irradiation and solventless conditions. The major assets of this methodology were the use of non-toxic organic medium, available catalyst, mild reaction condition, and good to excellent yield of desired products. All of the synthesized products were screened for their in vitro antioxidant activity using DPPH, ABTS, and Ferric-phenanthroline assays and it was found that most of them are potent antioxidant agents. Also, their butyrylcholinesterase inhibitory activity has been investigated in vitro. All tested compounds exhibited potential inhibitory activity toward BuChE when compared to standard reference drug galantamine, however, compounds 4r, 4u, 4 g and 4x gave higher butyrylcholinesterase inhibitory with IC50 values of 14.78 ± 0.65 µM, 16.18 ± 0.50 µM, 20.00 ± 0.50 µM, and 20.28 ± 0.08 µM respectively. On the other hand, we employed density functional theory (DFT), calculations to analyze molecular geometry and global reactivity descriptors, and MESP analysis to predict electrophilic and nucleophilic attacks. A quantitative structure-activity relationship (QSAR) investigation was conducted on the antioxidant and butyrylcholinesterase properties of 25 arylaminonaphthol derivatives, resulting in robust and satisfactory models. To evaluate their anti-Alzheimer's activity, compounds 4 g, 4q, 4r, 4u, and 4x underwent docking simulations at the active site of the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing why these compounds displayed superior activity, consistent with the biological findings.

Synthesis, characterisation, and in vitro antiparasitic activity of new flavanoidal tetrazinan-6'-ones and their binding study with calf thymus DNA using molecular modelling and spectroscopic techniques.

With the developing resistance to traditional antiparasitic medications, the purpose of this study was to efficiently develop a series of six noble flavanoidal tetrazinane-6'-one derivatives by a one-pot reaction pathway. FT-IR, 1HNMR, 13CNMR, and Mass spectra were employed for the structural elucidation of the synthesized compounds (7-12). Clinostomum complanatum, a parasite infection model that has been well-established, demonstrated that all the synthesized compounds are potent antiparasitic agents. DNA is the main target for various medicinal compounds. As a result, thestudy of how small molecules attach to DNA has received a lot of attention. In the present study, we have performed various biophysical techniques to determine the mode of binding of synthesized compounds (7-12) with calf thymus DNA (ct-DNA). It was observed from the UV-visible absorbance and fluorescence spectra that all synthesized compounds (7-12) form complexes with the ct-DNA. The value of binding constant (Kb) was obtained to be in the range of 4.36---24.50 × 103 M - 1 at 298 K. Competitive displacement assay with ethidium bromide (EB), CD spectral analysis, viscosity measurements, and in silico molecular docking confirmed that ligands (7-12) incorporate with ct-DNA through groove binding only. Molecular docking studies were performed for all synthesized compounds with the calf thymus DNA and it was found that all the newly synthesized compounds strongly bind with the chain B of DNA in the minor groove with the value of binding energy in the range of -8.54 to -9.04 kcal per mole and several hydrogen bonding interactions.

Integrating network pharmacology and Mendelian randomization to explore potential targets of matrine against ovarian cancer.

BACKGROUND: Matrine has been reported inhibitory effects on ovarian cancer (OC) cell progression, development, and apoptosis. However, the molecular targets of matrine against OC and the underlying mechanisms of action remain elusive. OBJECTIVE: This study endeavors to unveil the potential targets of matrine against OC and to explore the intricate relationships between these targets and the pathogenesis of OC. METHODS: The effects of matrine on the OC cells (A2780 and AKOV3) viability, apoptosis, migration, and invasion was investigated through CCK-8, flow cytometry, wound healing, and Transwell analyses, respectively. Next, Matrine-related targets, OC-related genes, and ribonucleic acid (RNA) sequence data were harnessed from publicly available databases. Differentially expressed analyses, protein-protein interaction (PPI) network, and Venn diagram were involved to unravel the core targets of matrine against OC. Leveraging the GEPIA database, we further validated the expression levels of these core targets between OC cases and controls. Mendelian randomization (MR) study was implemented to delve into potential causal associations between core targets and OC. The AutoDock software was used for molecular docking, and its results were further validated using RT-qPCR in OC cell lines. RESULTS: Matrine reduced the cell viability, migration, invasion and increased the cell apoptosis of A2780 and AKOV3 cells (P< 0.01). A PPI network with 578 interactions among 105 candidate targets was developed. Finally, six core targets (TP53, CCND1, STAT3, LI1B, VEGFA, and CCL2) were derived, among which five core targets (TP53, CCND1, LI1B, VEGFA, and CCL2) differential expressed in OC and control samples were further picked for MR analysis. The results revealed that CCND1 and TP53 were risk factors for OC. Molecular docking analysis demonstrated that matrine had good potential to bind to TP53, CCND1, and IL1B. Moreover, matrine reduced the expression of CCND1 and IL1B while elevating P53 expression in OC cell lines. CONCLUSIONS: We identified six matrine-related targets against OC, offering novel insights into the molecular mechanisms underlying the therapeutic effects of matrine against OC. These findings provide valuable guidance for developing more efficient and targeted therapeutic approaches for treating OC.

Green, facile synthesis and evaluation of unsymmetrical carbamide derivatives as antimicrobial and anticancer agents with mechanistic insights.

A very practical method for the synthesis of unsymmetrical carbamide derivatives in good to excellent yield was presented, without the need for any catalyst and at room temperature. Using a facile and robust protocol, fifteen unsymmetrical carbamide derivatives (9-23) bearing different aliphatic amine moieties were designed and synthesized by the reaction of secondary aliphatic amines with isocyanate derivatives in the presence of acetonitrile as an appropriate solvent in good to excellent yields. Trusted instruments like IR, mass spectrometry, NMR spectra, and elemental analyses were employed to validate the purity and chemical structures of the synthesized compounds. All the synthesized compounds were tested as antimicrobial agents against some clinically bacterial pathogens such as Salmonella typhimurium, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Compounds 15, 16, 17, 19 and 22 showed potent antimicrobial activity with promising MIC values compared to the positive controls. Moreover, compounds 15 and 22 provide a potent lipid peroxidation (LPO) of the bacterial cell wall. On the other hand, we investigated the anti-proliferative activity of compounds 9-23 against selected human cancerous cell lines of breast (MCF-7), colon (HCT-116), and lung (A549) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and pro-apoptotic protein markers. The results of MTT assay revealed that compounds 10, 13, 21, 22 and 23 possessed highly cytotoxic effects. Out of these, three synthesized compounds 13, 21 and 22 showed cytotoxicity with IC50 values (13, IC50 = 62.4 ± 0.128 and 22, IC50 = 91.6 ± 0.112 µM, respectively, on MCF-7), (13, IC50 = 43.5 ± 0.15 and 21, IC50 = 38.5 ± 0.17 µM, respectively, on HCT-116). Cell cycle and apoptosis/necrosis assays demonstrated that compounds 13 and 22 induced S and G2/M phase cell cycle arrest in MCF-7 cells, while only compound 13 had this effect on HCT-116 cells. Furthermore, compound 13 exhibited the greatest potency in inducing apoptosis in both cell lines compared to compounds 21 and 22. Docking studies indicated that compounds 10, 13, 21 and 23 could potentially inhibit enzymes and exert promising antimicrobial effects, as evidenced by their lower binding energies and various types of interactions observed at the active sites of key enzymes such as Sterol 14-demethylase of C. albicans, Dihydropteroate synthase of S. aureus, LasR of P. aeruginosa, Glucosamine-6-phosphate synthase of K. pneumenia and Gyrase B of B. subtilis. Moreover, 13, 21, and 22 demonstrated minimal binding energy and favorable affinity towards the active pocket of anticancer receptor proteins, including CDK2, EGFR, Erα, Topoisomerase II and VEGFFR. Physicochemical properties, drug-likeness, and ADME (absorption, distribution, metabolism, excretion, and toxicity) parameters of the selected compounds were also computed.

Pharmacokinetic and molecular docking studies to pyrimidine drug using Mn3O4 nanoparticles to explore potential anti-Alzheimer activity.

Alzheimer disease (AD) is the cause of dementia and accounts for 60-80% cases. Tumor Necrosis Factor-alpha (TNF-α) is a multifunctional cytokine that provides resistance to infections, inflammation, and cancer. It developed as a prospective therapeutic target against multiple autoimmune and inflammatory disorders. Cholinergic insufficiency is linked to Alzheimer's disease, and several cholinesterase inhibitors have been created to treat it, including naturally produced inhibitors, synthetic analogs, and hybrids. In the current study, we tried to prepared compounds may also support the discovery and development of novel therapeutic and preventative drugs for Alzheimer's using manganese tetroxide nanoparticles (Mn3O4-NPs) as a catalyst to generate compounds with excellent reaction conditions. The Biginelli synthesis yields 4-(4-cyanophenyl)-6-oxo-2-thioxohexahydropyrimidine-5-carbonitrile when the 4-cyanobenzaldehyde, ethyl cyanoacetate, and thiourea were coupled with Mn3O4-NPs to produce compound 1. This multi-component method is non-toxic, safe, and environmentally friendly. The new approach reduced the amount of chemicals used and preserved time. Compound 1 underwent reactions with methyl iodide, acrylonitrile, chloroacetone, ethyl chloroacetate, and chloroacetic acid/benzaldehyde, each of the synthetized compounds was docked with TNF-α converting enzyme. These compounds may also support the discovery and development of novel therapeutic and preventative drugs for Alzheimer's disease. The majority of the produced compounds demonstrated pharmacokinetic features, making them potentially attractive therapeutic candidates for Alzheimer's disease treatment.

Synthesis, pharmacological evaluation, and in silico study of new 3-furan-1-thiophene-based chalcones as antibacterial and anticancer agents.

New 3-furan-1-thiophene-based chalcones were synthesized, characterized and pharmacologically evaluated as antibacterial and anticancer agents against two bacterial species; Gram-positive (Streptococcus pyogenes) and Gram-negative (Pseudomonas aeruginosa). All tested final compounds were active against the two bacterial species; S. pyogenes and P . aeruginosa. Especially compound AM4 showed large inhibition zone (27.13 and 23.30 mm), respectively. Using the DPPH assay, the new chalcones were evaluated for their free radical scavenging activity and found to reach up to 90 %, accomplished at a test concentration of 200 µg/mL. Furthermore, the chalcone derivatives were investigated against two breast cell lines; MCF-7 (cancerous) and MCF-10A (non-cancerous). Compound AM4 showed potent anticancer activity (IC50 = 19.354 µg/mL) in comparison to the other tested chalcone derivatives. In silico study was achieved using the PyRx AutoDock Vina software (0.8) to study the interaction types between the new hits and the binding sites of targeted proteins; glucosamine-6-phosphate synthase and tubulin, the target for antibacterial and anticancer drugs, respectively. Based on the molecular docking results the tested chalcones bind to the active pocket of the respective proteins, which support the in vitro results. In conclusion, 3-furan-1-thiophene-based chalcones could serve as new hits in the discovery of novel anticancer and/or antibacterial drugs.

Exploring the potential mechanism of WuFuYin against hypertrophic scar using network pharmacology and molecular docking.

BACKGROUND: Hypertrophic scar (HTS) is dermal fibroproliferative disorder, which may cause physiological and psychological problems. Currently, the potential mechanism of WuFuYin (WFY) in the treatment of HTS remained to be elucidated. AIM: To explore the potential mechanism of WFY in treating HTS. METHODS: Active components and corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. HTS-related genes were obtained from the GeneCards, DisGeNET, and National Center for Biotechnology Information. The function of targets was analyzed by performing Gene Ontology and Kyoto Encyclopaedia of Genes and Genome (KEGG) enrichment analysis. A protein + IBM-protein interaction (PPI) network was developed using STRING database and Cytoscape. To confirm the high affinity between compounds and targets, molecular docking was performed. RESULTS: A total of 65 core genes, which were both related to compounds and HTS, were selected from multiple databases. PPI analysis showed that CKD2, ABCC1, MMP2, MMP9, glycogen synthase kinase 3 beta (GSK3B), PRARG, MMP3, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG) were the hub targets and MOL004941, MOL004935, MOL004866, MOL004993, and MOL004989 were the key compounds of WFY against HTS. The results of KEGG enrichment analysis demonstrated that the function of most genes were enriched in the PI3K-Akt pathway. Moreover, by performing molecular docking, we confirmed that GSK3B and 8-prenylated eriodictyol shared the highest affinity. CONCLUSION: The current findings showed that the GSK3B and cyclin dependent kinase 2 were the potential targets and MOL004941, MOL004989, and MOL004993 were the main compounds of WFY in HTS treatment.

Molecular Mechanism of Cynodon dactylon Phytosterols Targeting MAPK3 and PARP1 to Combat Epithelial Ovarian Cancer: A Multifaceted Computational Approach.

Epithelial Ovarian Cancer (EOC) presents a global health concern, necessitating the development of innovative therapeutic strategies to combat its impact. This study was employed to investigate the unexplored therapeutic efficacy of Cynodon dactylon phytochemicals against EOC using a multifaceted computational approach. A total of 19 out of 89 rigorously curated phytochemicals were assessed as potential drug targets via ADMET profiling, while protein-protein interaction analysis scrutinized the top 20 hub genes among 264 disease targets, revealing their involvement in cancer-related pathways and underscoring their significance in EOC pathogenesis. In molecular docking, Stigmasterol acetate showed the highest binding affinity (-10.9 kcal/mol) with Poly [ADP-ribose] polymerase-1 (PDB: 1UK1), while Arundoin and Beta-Sitosterol exhibited strong affinities (-10.4 kcal/mol and -10.1 kcal/mol, respectively); additionally, Beta-Sitosterol interacting with Mitogen-activated protein kinase 3 (PDB: 4QTB) showed a binding affinity of -10.1 kcal/mol, forming 2 hydrogen bonds and a total of 10 bonds with 10 residues. Molecular dynamics simulations exhibited the significant structural stability of the Beta-Sitosterol-4QTB complex with superior binding free energy (-36.61 kcal/mol) among the three complexes. This study identified C. dactylon phytosterols, particularly Beta-Sitosterol, as effective in targeting MAPK3 and PARP1 to combat EOC, laying the groundwork for further experimental validation and drug development efforts.

Renshen Yangrong decoction for secondary malaise and fatigue: network pharmacology and Mendelian randomization study.

Background: Renshen Yangrong decoction (RSYRD) has been shown therapeutic effects on secondary malaise and fatigue (SMF). However, to date, its bioactive ingredients and potential targets remain unclear. Purpose: The purpose of this study is to assess the potential ingredients and targets of RSYRD on SMF through a comprehensive strategy integrating network pharmacology, Mendelian randomization as well as molecular docking verification. Methods: Search for potential active ingredients and corresponding protein targets of RSYRD on TCMSP and BATMAN-TCM for network pharmacology analysis. Mendelian randomization (MR) was performed to find therapeutic targets for SMF. The eQTLGen Consortium (sample sizes: 31,684) provided data on cis-expression quantitative trait loci (cis-eQTL, exposure). The summary data on SMF (outcome) from genome-wide association studies (GWAS) were gathered from the MRC-IEU Consortium (sample sizes: 463,010). We built a target interaction network between the probable active ingredient targets of RSYRD and the therapeutic targets of SMF. We next used drug prediction and molecular docking to confirm the therapeutic value of the therapeutic targets. Results: In RSYRD, network pharmacology investigations revealed 193 possible active compounds and 234 associated protein targets. The genetically predicted amounts of 176 proteins were related to SMF risk in the MR analysis. Thirty-seven overlapping targets for RSYRD in treating SMF, among which six (NOS3, GAA, IMPA1, P4HTM, RB1, and SLC16A1) were prioritized with the most convincing evidence. Finally, the 14 active ingredients of RSYRD were identified as potential drug molecules. The strong affinity between active components and putative protein targets was established by molecular docking. Conclusion: This study revealed several active components and possible RSYRD protein targets for the therapy of SMF and provided novel insights into the feasibility of using Mendelian randomization for causal inference between Chinese medical formula and disease.

Investigating the Potential of 2-Ethylbutyl-(Phenoxy)phosphoryl-D-Alaninate Against RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2.

There was an emergency call globally when COVID-19 was detected in December 2019. The SARS-CoV-2 virus, a modified virus, is what causes this contagious disease. Although research is being conducted throughout the world, the main target is still to find the promising candidate to target RNA-dependent RNA polymerase (RdRp) to provide possible drug against COVID-19. Aim of this work is to find a molecule to inhibit the translational process of viral protein synthesis. Density Functional Theory calculations revealed information about the formation of the desired ligand (RD). Molecular docking of RD with RdRp was performed and compared with some reported molecules and the data revealed that RD had the best docking score with RdRp (-6.7 kcal/mol). Further, molecular dynamics (MD) simulations of RD with RdRp of SARS-CoV-2 revealed the formation of stable complex with a maximum number of seven hydrogen bonds. Root mean square deviations values are in acceptable range and root mean square fluctuations has less fluctuation indicate stable complex formation. Further, based on MM-GBSA calculation, RD formed a stable complex with RdRp of nCoV with ΔG° of -12.28 kcal·mol-1.

Roselle (Hibiscus sabdariffa L.) extract as an adjunct to valsartan in patients with mild chronic kidney disease: A double-blind randomized controlled clinical trial.

Objective: The objective of this study was to evaluate the effectiveness of Hibiscus sabdariffa L. extract (HS) as an adjunct to valsartan in the treatment of high blood pressure in patients with mild chronic kidney disease (CKD). Materials and Methods: This trial was conducted in Gorgan, Iran. Seventy-two participants with CKD and high blood pressure were randomly assigned to either the HS group, receiving a 350 mg pill every 12 hr for 90 days along with 40 mg of valsartan every 12 hr, or the control group (40 mg valsartan + 12.5 mg hydrochlorothiazide). The primary objective was to assess the improvement of hypertension, while secondary objectives included the evaluation of proteinuria, albuminuria, kidney function, lipid profile, and electrolyte levels. Molecular docking analysis was performed to examine the mechanisms of action of the isolated components of HS. Results: Out of 80 initial participants, 72 were included in the analysis. Both groups showed a significant reduction in blood pressure (p<0.001). The HS group demonstrated a statistically significant decrease in lipid profile (p<0.001). There were no statistically significant differences between the groups regarding the reduction of renal markers. Molecular docking analysis revealed that the compounds present in HS, particularly its anthocyanins and flavonoids, exhibited greater angiotensin-converting enzyme (ACE) inhibitory potential than hydrochlorothiazide in both domains. Moreover, the compounds met the criteria for drug likeness and Lipinski rules. Conclusion: Adjunctive therapy with HS showed promising results in reducing hypertension and improving lipid profile in patients with CKD.

Optimization, gene cloning, expression, and molecular docking insights for enhanced cellulase enzyme production by Bacillus amyloliquefaciens strain elh1.

BACKGROUND: In this study, we isolated a cellulase-producing bacterium, Bacillus amyloliquefaciens strain elh, from rice peel. We employed two optimization methods to enhance the yield of cellulase. Firstly, we utilized a one-variable-at-a-time (OVAT) approach to evaluate the impact of individual physical and chemical parameters. Subsequently, we employed response surface methodology (RSM) to investigate the interactions among these factors. We heterologously expressed the cellulase encoding gene using a cloning vectorin E. coli DH5α. Moreover, we conducted in silico molecular docking analysis to analyze the interaction between cellulase and carboxymethyl cellulose as a substrate. RESULTS: The bacterial isolate eh1 exhibited an initial cellulase activity of 0.141 ± 0.077 U/ml when cultured in a specific medium, namely Basic Liquid Media (BLM), with rice peel as a substrate. This strain was identified as Bacillus amyloliquefaciens strain elh1 through 16S rRNA sequencing, assigned the accession number OR920278 in GenBank. The optimal incubation time was found to be 72 h of fermentation. Urea was identified as the most suitable nitrogen source, and dextrose as the optimal sugar, resulting in a production increase to 5.04 ± 0.120 U/ml. The peak activity of cellulase reached 14.04 ± 0.42 U/ml utilizing statistical optimization using Response Surface Methodology (RSM). This process comprised an initial screening utilizing the Plackett-Burman design and further refinement employing the BOX -Behnken Design. The gene responsible for cellulase production, egl, was effectively cloned and expressed in E. coli DH5α. The transformed cells exhibited a cellulase activity of 22.3 ± 0.24 U/ml. The egl gene sequence was deposited in GenBank with the accession number PP194445. In silico molecular docking revealed that the two hydroxyl groups of carboxymethyl cellulose bind to the residues of Glu169 inside the binding pocket of the CMCase. This interaction forms two hydrogen bonds, with an affinity score of -5.71. CONCLUSIONS: Optimization of cultural conditions significantly enhances the yield of cellulase enzyme when compared to unoptimized culturing conditions. Additionally, heterologous expression of egl gene showed that the recombinant form of the cellulase is active and that a valid expression system can contribute to a better yield of the enzyme.

Investigating the mechanism of Fuling-Banxia-Dafupi in the treatment of diabetic kidney disease using network pharmacology and molecular docking.

Go deeply into the molecular mechanism of Fuling-Banxia-Dafupi in the treatment of diabetic kidney disease (DKD) by network pharmacology and molecular docking. Fuling-Banxia-Dafupi is a pair of traditional Chinese medicine for diabetic kidney disease, which can slow down the development of diabetic kidney disease. Screening active components and targets of Fuling-Banxia-Dafupi using the TCMSP database. The Uniprot database was also used to identify effective drug targets. DKD-related Targets were retrieved from the Gene Cards database, and the overlap between these targets and Fuling-Banxia-Dafupi was obtained. GO and KEGG pathway concentration analyses were showed using Metascape, and the results were presented by the microcredit platform. A total of 616 active ingredients and targets were confrimed and intersected with 3,951 diabetic neuropathy-related targets, resulting in 306 common targets. Baicalein and cerevisterol are the core components of Fuling-Banxia-Dafupi, and the key targets are TP53, SRC, and STAT 3. PI3K-Akt signalling pathway is an important pathway. The molecular docking indicated that its main active components and target proteins have good binding activity.

Synthesis, anti-diabetic profiling and molecular docking studies of 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones.

Aim: To synthesize novel more potent anti-diabetic agents. Methodology: A simple cost effective Hantzsch's synthetic strategy was used to synthesize 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones. Results: Fifteen new 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones were established to check their anti-diabetic potential. From alpha(α)-amylase inhibition, anti-glycation and anti-oxidant activities it is revealed that most of the compounds possess good anti-diabetic potential. All tested compounds were found to be more potent anti-diabetic agents via anti-glycation mode. The results of α-amylase and anti-oxidant inhibition revealed that compounds are less active against α-amylase and anti-oxidant assays. Conclusion: This study concludes that introduction of various electron withdrawing groups at the aryl ring and substitution of different functionalities around thiazolone nucleus could help to find out better anti-diabetic drug.

Diabetes is a most spreading chronicle disease effecting millions of peoples across the globe every year and this number increases day by day. To cure the human population from this dilemma, we had synthesized, characterized and evaluated the anti-diabetic behavior of our synthesized compounds. α-Amylase, in vitro anti-glycation and anti-oxidant assays were performed to find out good lead for Diabetes Mellitus. All tested compounds were found to be excellent anti-glycating agents with IC₅₀ values far better than standard amino-guanidine (IC₅₀ = 3.582 ± 0.002 µM). Compound 4m was most efficient glycation inhibitor (IC₅₀ = 1.095 ± 0.002 µM). Cytotoxicity of all compounds was determined with in vitro hemolytic assay and found all compounds safe and bio-compatible to humans at all tested concentrations. The inhibition potential was also examined with theoretical docking studies to support our experimental results against human pancreatic alpha-amylase (HPA) and human serum albumin (HSA) proteins. All compounds showed excellent binding affinity with HSA active pockets however, only compound 4h and 4k binding affinity was good with HPA.

Computational discovery of AKT serine/threonine kinase 1 inhibitors through shape screening for rheumatoid arthritis intervention.

Rheumatoid Arthritis (RA) is a chronic, symmetrical inflammatory autoimmune disorder characterized by painful, swollen synovitis and joint erosions, which can cause damage to bone and cartilage and be associated with progressive disability. Despite expanded treatment options, some patients still experience inadequate response or intolerable adverse effects. Consequently, the treatment options for RA remain quite limited. The enzyme AKT1 is crucial in designing drugs for various human diseases, supporting cellular functions like proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. Therefore, AKT serine/threonine kinase 1 is considered crucial for targeting therapeutic strategies aimed at mitigating RA mechanisms. In this context, directing efforts toward AKT1 represents an innovative approach to developing new anti-arthritis medications. The primary objective of this research is to prioritize AKT1 inhibitors using computational techniques such as molecular modeling and dynamics simulation (MDS) and shape-based virtual screening (SBVS). A combined SBVS approach was employed to predict potent inhibitors against AKT1 by screening a pool of compounds sourced from the ChemDiv and IMPPAT databases. From the SBVS results, only the top three compounds, ChemDiv_7266, ChemDiv_2796, and ChemDiv_9468, were subjected to stability analysis based on their high binding affinity and favorable ADME/Tox properties. The SBVS findings have revealed that critical residues, including Glu17, Gly37, Glu85, and Arg273, significantly contribute to the successful binding of the highest-ranked lead compounds at the active site of AKT1. This insight helps to understand the specific binding mechanism of these leads in inhibiting RA, facilitating the rational design of more effective therapeutic agents.

Construction of IRAK4 inhibitor activity prediction model based on machine learning.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a crucial serine/threonine protein kinase that belongs to the IRAK family and plays a pivotal role in Toll-like receptor (TLR) and Interleukin-1 receptor (IL-1R) signaling pathways. Due to IRAK4's significant role in immunity, inflammation, and malignancies, it has become an intriguing target for discovering and developing potent small-molecule inhibitors. Consequently, there is a pressing need for rapid and accurate prediction of IRAK4 inhibitor activity. Leveraging a comprehensive dataset encompassing activity data for 1628 IRAK4 inhibitors, we constructed a prediction model using the LightGBM algorithm and molecular fingerprints. This model achieved an R2 of 0.829, an MAE of 0.317, and an RMSE of 0.460 in independent testing. To further validate the model's generalization ability, we tested it on 90 IRAK4 inhibitors collected in 2023. Subsequently, we applied the model to predict the activity of 13,268 compounds with docking scores less than - 9.503 kcal/mol. These compounds were initially screened from a pool of 1.6 million molecules in the chemdiv database through high-throughput molecular docking. Among these, 259 compounds with predicted pIC50 values greater than or equal to 8.00 were identified. We then performed ADMET predictions on these selected compounds. Finally, through a rigorous screening process, we identified 34 compounds that adhere to the four complementary drug-likeness rules, making them promising candidates for further investigation. Additionally, molecular dynamics simulations confirmed the stable binding of the screened compounds to the IRAK4 protein. Overall, this work presents a machine learning model for accurate prediction of IRAK4 inhibitor activity and offers new insights for subsequent structure-guided design of novel IRAK4 inhibitors.

Identification of diagnose related therapeutic targets of Danggui buxue decoction in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the fastest growing neurological disease. Currently, there is no disease-modifying therapy to slow the progression of the disease. Danggui buxue decoction (DBD) is widely used in the clinic because of its therapeutic effect. However, little is known about the molecular mechanism of DBD against PD. This study intends to explore the possible molecular mechanisms involved in DBD treatment of PD based on network pharmacology, and provide potential research directions for future research. METHODS: Firstly, the active components and target genes of DBD were screened from the traditional Chinese medicine systems pharmacology (TCMSP), DrugBank and UniProt database. Secondly, target genes of PD were identified from the (GEO) dataset, followed by identification of common target genes of DBD and PD. Thirdly, analysis of protein-protein interaction (PPI), functional enrichment and diagnosis was performed on common target genes, followed by correlation analysis between core target genes, immune cell, miRNAs, and transcription factors (TFs). Finally, molecular docking between core target genes and active components, and real-time PCR were performed. RESULTS: A total of 72 common target genes were identified between target genes of DBD and target genes of PD. Among which, 11 target genes with potential diagnostic value were further identified, including TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2. The combinations with the best docking binding were identified, including kaempferol-AKT1/HMOX1/NOS2/NOS3, quercetin-AKT1/ERBB2/IL1B/HMOX1/MMP9/TP53/NOS3/TGFB1. Moreover, IL1B and NOS2 respectively positively and negatively correlated with neutrophil and Type 1 T helper cell. Some miRNA-core target gene regulatory pairs were identified, such as hsa-miR-185-5p-TP53/TGFB1/RELA/MAPK14/IL1B/ERBB2/AKT1 and hsa-miR-214-3p-NOS3. These core target genes were significantly enriched in focal adhesion, TNF, HIF-1, and ErbB signaling pathway. CONCLUSION: Diagnostic TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2 may be considered as potential therapeutic targets of DBD in the treatment of PD.