ADMET Analysis Research Articles

Exploring the Antiviral Potential of Artemisia annua Through JAK-STAT Pathway Targeting: A Network Pharmacology Approach

Background: Artemisia annua, a plant with antiviral potential, has shown promise against various viral infections, yet its mechanisms of action are not fully understood. This study explores A. annua’s antiviral effects using network pharmacology and molecular docking, focusing on key active compounds and their interactions with viral protein targets, particularly within the JAK-STAT signaling pathway—a critical mediator of immune responses to viral infections. Methods: From the TCMSP database, we identified eight active compounds and 335 drug targets for A. annua, with 19 intersecting targets between A. annua compounds and viral proteins. A protein–protein interaction (PPI) network highlighted 10 key hub genes, analyzed further through Gene Ontology (GO) and KEGG pathways to understand their immune and antiviral roles. ADMET properties of the active compound Patuletin (MOL004112) were assessed, followed by 200 ns molecular dynamics simulations to examine its stability in complex with JAK2. Results: PPI analysis identified JAK2, MAPK3, MAPK1, JAK1, PTPN1, HSPA8, TYK2, RAF1, MAPT, and HMOX1 as key hub genes, with JAK2 emerging as a critical regulator of immune and antiviral pathways. ADMET analysis confirmed Patuletin’s favorable pharmacokinetic properties, and molecular dynamics simulations showed a stable Patuletin-JAK2 complex, with FEL analysis indicating minimal disruption to JAK2’s intrinsic flexibility. Conclusions: These findings highlight JAK2 as a promising target in the antiviral activity of A. annua compounds, particularly Patuletin, supporting its potential as an antiviral agent and providing a foundation for further research on A. annua’s therapeutic applications.

Integrated virtual screening and MD simulation study to discover potential inhibitors of mycobacterial electron transfer flavoprotein oxidoreductase.

Tuberculosis (TB) continues to be a major global health burden, with high incidence and mortality rates, compounded by the emergence and spread of drug-resistant strains. The limitations of current TB medications and the urgent need for new drugs targeting drug-resistant strains, particularly multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, underscore the pressing demand for innovative anti-TB drugs that can shorten treatment duration. This has led to a focus on targeting energy metabolism of Mycobacterium tuberculosis (Mtb) as a promising approach for drug discovery. This study focused on repurposing drugs against the crucial mycobacterial protein, electron transfer flavoprotein oxidoreductase (EtfD), integral to utilizing fatty acids and cholesterol as a carbon source during infection. The research adopted an integrative approach, starting with virtual screening of approved drugs from the ZINC20 database against EtfD, followed by molecular docking, and concluding with molecular dynamics (MD) simulations. Diacerein, levonadifloxacin, and gatifloxacin were identified as promising candidates for repurposing against TB based on their strong binding affinity, stability, and interactions with EtfD. ADMET analysis and anti-TB sensitivity predictions assessed their pharmacokinetic and therapeutic potential. Diacerein and levonadifloxacin, previously unexplored in anti-tuberculous therapy, along with gatifloxacin, known for its efficacy in drug-resistant TB, have broad-spectrum antimicrobial properties and favorable pharmacokinetic profiles, suggesting potential as alternatives to current TB treatments, especially against resistant strains. This study underscores the efficacy of computational drug repurposing, highlighting bacterial energy metabolism and lipid catabolism as fruitful targets. Further research is necessary to validate the clinical suitability and efficacy of diacerein, levonadifloxacin, and gatifloxacin, potentially enhancing the arsenal against global TB.

Insilico discovery of novel Phosphodiesterase 4 (PDE4) inhibitors for the treatment of psoriasis: Insights from computer aided drug design approaches.

Psoriasis is chronic immune-mediated inflammatory disorder characterized by various comorbidities, erythematous plaques with silvery scale which can lead to psoriatic arthritis. The phosphodiesterase 4 (PDE4) protein is a potential drug target to control Psoriasis. In the current study, pharmacophore-based virtual screening of Diversity library of ChemDiv database was first performed, and then the screened hits were docked to the active site of PDE4 to choose the best binding modes. Forty-six hits generated during the virtual screening were prepared and docked to the PDE4 receptor by SP docking module of glide. The binding affinities of the selected hits were calculated by molecular docking and based on the affinities, ten hits were selected for the bioactivity scores prediction and ADMET analysis. Based on the ADMET profiling, four hits D356-2630, C700-2058, G842-0420 and F403-0203 were processed to MD simulations for stability analysis. The outcomes showed that these compounds showed strong binding with proteins with better binding free energies. Based on the results of our study, we proposed that these hits can function as lead in the biological assays and in vitro studies are required to develop the novel drug candidates.

In Silico Identification of Promising PDE5 Inhibitors Against Hepatocellular Carcinoma Among Natural Derivatives: A Study Involving Docking and ADMET Analysis.

Hepatocellular carcinoma (HCC) represents a significant worldwide health challenge due to its high mortality rate, underscoring the need for advanced therapeutic strategies. This study employs a computer-based method to identify potential phosphodiesterase 5 (PDE5) inhibitors from a library of approved IBS_Scaff 532 natural compounds. PDE5 inhibitors have gained attention for their potential anti-tumor effects. Using molecular docking simulations, the researchers assessed how well these compounds bind to the PDE5 enzyme, which regulates cellular cGMP pathways. Additionally, ADMET profiling predicted the pharmacological and safety properties of candidate inhibitors. Notably, compounds like IBS_NC-0322 and IBS_NC-0320 exhibited favorable ADMET properties and strong binding affinities. These findings suggest their potential as therapeutic agents for treating HCC. While in silico methods serve as valuable screening tools, subsequent experimental validation and clinical trials are essential for confirmation.

Discovery of key molecular signatures for diagnosis and therapies of glioblastoma by combining supervised and unsupervised learning approaches.

Glioblastoma (GBM) is the most malignant brain cancer and one of the leading causes of cancer-related death globally. So, identifying potential molecular signatures and associated drug molecules are crucial for diagnosis and therapies of GBM. This study suggested GBM-causing ten key genes (ASPM, CCNB2, CDK1, AURKA, TOP2A, CHEK1, CDCA8, SMC4, MCM10, and RAD51AP1) from nine transcriptomics datasets by combining supervised and unsupervised learning results. Differential expression patterns of key genes (KGs) between GBM and control samples were verified by different independent databases. Gene regulatory network (GRN) detected some important transcriptional and post-transcriptional regulators for KGs. The KGs-set enrichment analysis unveiled some crucial GBM-causing molecular functions, biological processes, cellular components, and pathways. The DNA methylation analysis detected some hypo-methylated CpG sites that might stimulate the GBM development. From the immune infiltration analysis, we found that almost all KGs are associated with different immune cell infiltration levels. Finally, we recommended KGs-guided four repurposable drug molecules (Fluoxetine, Vatalanib, TGX221 and RO3306) against GBM through molecular docking, drug likeness, ADMET analyses and molecular dynamics simulation studies. Thus, the discoveries of this study could serve as valuable resources for wet-lab experiments in order to take a proper treatment plan against GBM.

Exploring phytochemical inhibitors of protein kinase C alpha for therapeutic targeting of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by neurodegeneration linked to amyloid-β (Aβ) plaques and tau protein tangles. Protein kinase C alpha (PKCα) plays a crucial role in modulating amyloid-β protein precursor (AβPP) processing, potentially mitigating AD progression. Consequently, PKCα stands out as a promising target for AD therapy. Despite the identification of numerous inhibitors, the pursuit of more effective and precisely targeted PKCα inhibitors remains crucial. In this study, we employed an integrated virtual screening approach of molecular docking and molecular dynamics (MD) simulations to identify phytochemical inhibitors of PKCα from the IMPPAT database. Molecular docking screening via InstaDock identified compounds with strong binding affinities to PKCα. Subsequent ADMET and PASS analyses filtered out compounds with favorable pharmacokinetic profiles. Interaction analysis using Discovery Studio Visualizer and PyMOL further elucidated binding conformations of selected compounds with PKCα. Top hits underwent 200 ns MD simulations using GROMACS to validate stability of the interactions. Finally, we propose two phytochemicals, Kammogenin and Imperialine, with appreciable drug-likeliness and binding potential with PKCα. Taken together, the findings suggest Kammogenin and Imperialine as potential PKCα inhibitors, highlighting their therapeutic promise for AD after further validation.

Novel indole based fused triazole-thiadiazole derivatives as anti-diabetic agents: in vitro and in silico approaches.

Aim: The current research presents novel library of indole derived fused triazole-thiadiazole derivatives (1-17) for treatment of diabetes mellitus.Methods & results: These compounds were synthesized by treating 2-(1H-indol-3-yl)acetic acid with hydrazinecarbothiohydrazide followed by treating the resultant compound with substituted benzoic acid. Structural validation was achieved spectroscopically (1HNMR, 13CNMR and HREI-MS). The synthesized compounds were subjected to biological evaluation to assess their potential as anti-diabetic. Molecular docking study was employed to investigate the binding interactions of these analogs with relevant proteins. ADMET analysis was used to predict their drug-like properties. Notably, compound-10 (IC50 = 1.27±1.25 and 2.18±2.45 μM) bearing para-substituted F atom exhibited the highest potency due to strong inhibitory interactions through hydrogen bonding.Conclusion: This study identifies promising compounds with anti-diabetic activity, paving the way for the treatment of diabetes mellitus.

Molecular mechanisms of acquired idiopathic generalized anhidrosis: differential gene expression and potential therapeutic targets

Eccrine sweat glands are essential for thermoregulation. Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder characterized by the absence of sweating, leading to severe complications like heatstroke and skin dryness. The underlying etiology remains unknown, complicating diagnosis and treatment. This study aimed to elucidate the genetic mechanisms of AIGA by analysing the gene expression in eccrine sweat glands using the GSE193125 dataset from the NCBI Gene Expression Omnibus (GEO). This study identified differentially expressed genes (DEGs) (genes that show statistically significant differences in expression levels in AIGA), with JUN and CCN1 significantly downregulated in anhidrotic lesions of AIGA patients. Receiver operating characteristic (ROC) curve demonstrated the accuracy of these genes in classification (JUN = 0.88 and CCN1 = 0.77). Gene and protein interaction networks which are defined as networks of physical interactions between genes and proteins, constructed using GeneMANIA and STRING, revealed substantial physical interactions among them. Gene set enrichment analysis highlighted the neuroinflammatory and estrogen receptor signaling pathways are associated with this condition, suggesting hormonal regulation’s role in the anhidrosis mechanism. Key miRNAs, including hsa-let-7b-5p, hsa-miR-10b-5p, and hsa-miR-124-3p, are associated with the DEGs, underscoring the importance of post-transcriptional and transcriptional regulation. Through the Drug Gene Interaction Database (DGIdb), ciprofibrate is identified as a potential therapeutic agent targeting the JUN gene. Molecular docking confirmed a strong binding affinity between ciprofibrate and JUN, suggesting ciprofibrate could modulate JUN activity and regulate AIGA symptoms. ADMET analysis, which refers to the assessment of absorption, distribution, metabolism, excretion, and toxicity of a drug or compound, is crucial for evaluating its pharmacokinetic and safety profile. The analysis indicated that ciprofibrate has favourable pharmacokinetic properties and a relatively safe toxicity profile. This comprehensive bioinformatics approach, integrating gene expression analysis, miRNA identification, and drug interaction, provides valuable insights into anhidrosis molecular pathology and highlights ciprofibrate’s potential as a targeted therapeutic strategy. Despite limitations, including a small sample size and reliance on computational predictions, this study paves the way for further research and potential therapeutic interventions for AIGA.

Insight from molecular modeling and ADMET analysis: Design, synthesis and in vitro acetylcholinesterase and butyrylcholinesterase assessment of thiazolidinone containing benzoxazole hybrids derivatives

Alzheimer's disease (AD) is a brain disorder medically defined as loss of memory and analytical reasoning abilities of an infected person. The adult or aged peoples are more likely to be adversely affected by this disease. Following this prospect, this study is conducted to synthesize a novel class of (Z)-2-(((Z)-2-(benzo[d]oxazol-2-ylthio)-1-phenylethylidene)hydrazono)-3-phenylthiazolidin-4-one based derivatives and evaluate its performance towards the treatment of AD. This study showed the better results when compared to the inhibition potential of the standard drug Donepezil against AChE (IC50= 4.10 ± 1.05 µM) and against BuChE (IC50=6.59 ± 1.63 µM), the inhibition potential shown by benzimidazole based thiadiazole scaffolds against the targeted enzymes is of wide range. The inhibition potential of all the scaffolds against AChE ranged from 2.89 ± 0.65 µM to 19.04 ± 0.49 µM and against BuChE ranged from 3.70 ± 0.98 µM to 23.19 ± 0.71 µM. Moreover, to investigate the binding interaction of effective scaffolds against the active sites of AChE and BuChE, molecular docking studies were carried out and the analysis data evaluated the substantial binding interaction of scaffolds against the targeted enzymes. The structural characteristic of each scaffold is determined by using different spectroscopic techniques. In this work only three analogues found to be the most active having the observed IC50 values 7d, 3.05 ± 0.19 µM, 2.90 ± 0.87 µM(for BuChE), 7g, 3.88 ± 0.32 µM(for AChE), 4.98 ± 0.54 µM(for BuChE), 7k 2.89 ± 0.65 µM(for AChE), 3.70 ± 0.98 µM(for BuChE). Furthermore, the selected analogues considered for In-Vivo and cytotoxic study as well as structure modification carried out in search of more active analogues.

Evaluation of 1,3,4-thiadiazole and 1,3-thiazolidine-4-one binary molecules against the SARS-CoV-2 receptor: DFT study, PASS prediction, ADMET analysis, molecular docking, and ADMET optimization

Evaluation of 1,3,4-thiadiazole and 1,3-thiazolidine-4-one binary molecules against the SARS-CoV-2 receptor: DFT study, PASS prediction, ADMET analysis, molecular docking, and ADMET optimization

Efficient synthesis and molecular docking of new organoselenium and organosulphur compounds as dual inhibitors for the therapy of Alzheimer's disease as well as Diabetes Mellitus

There are several oxidative stress-related pathways interconnecting Alzheimer's disease and type II diabetes, two public health problems worldwide. Therefore, development of potential multifunctional agents for dual therapy of AD and T2D has received much attention. The present study was aimed to synthesize a new selenocarbonyl and thiocarbonyl compounds and evaluating multifunctional ability of them in the AD and T2D dual therapy. [(PhP(Se)(μ-Se)]2, the selenium counterpart of the well-known sulfur transfer Lawesson's reagent, is a useful reagent for the synthesis of selenocarbonyl compounds. For the conversion of various carbonyl compounds into thiocarbonyl derivatives was formulated by its reaction with LR, [(p-MeOC6H4)P(S)(μ-S)]2. The reactions are carried out under mild conditions and afforded the seleno and thio compounds in good yields. By measuring the newly created compounds' overall antioxidant capacity, iron-reducing ability, and scavenging activity against DPPH and ABTS radicals, they were investigated as antioxidant molecules. Additionally, all the compounds were subjected to further investigation by testing their acetylcholinesterase, α-amylase and α-glucosidase inhibiting activity. According to our findings, the amide derivatives exhibited more promising biological inhibitory actions in comparison to the other compounds. With a total antioxidant capacity (TAC) of 75.11 ± 0.04 mg gallic acid/gm, an iron-reducing power (IRP) of 69.86 ± 0.04 µg/mL, a DPPH radical-scavenging activity (%) of 55.89 ± 0.03 (IC50 = 6.19 ± 0.03 µg/ml), and an ABTS radical-scavenging activity (%) of 61.14 ± 0.03 (IC50 = 4.97 ± 0.06 µg/mL), benzoselenoamide derivative 11b in particular showed the highest antioxidant activities when compared to ascorbic acid. It also affected the activity of acetylcholinesterase through competitive inhibition, which was on par with Donepezil as indicated by in vitro percentage of inhibition 57.44 ± 0.07 % (IC50 = 5.13 ± 0.03 µg/mL). Additionally, it exhibited a comparable level of inhibition to Acarbose in the in vitro percentage of inhibition for α-amylase and α-glucosidase activity, 53.17 ± 0.03 (IC50 = 4.32 ± 0.02) and 42.92 ± 0.03 (IC50 = 2.99 ± 0.02) respectively. Furthermore, molecular docking calculations were made to explain the dual inhibitors for the therapy of Alzheimer's as well as Diabetes Mellitus for all synthesized compounds. In silco docking results revealed that compound 11b were the top docked bioactive compounds against the target proteins (AChE as a cholinergic enzyme and 11-Beta-Hydroxysteroid dehydrogenase-1(11β-HSD1)). After these calculations, ADMET analysis was performed to examine the drug properties of all novel compounds. Overall, the results demonstrated that the organoselenium-based compounds might serve as possible drugs for the therapy of Alzheimer's disease as well as Diabetes Mellitus.

Novel 5-Fluorouracil analogues versus perfluorophenyl ureas as potent anti-breast cancer agents: Design, robust synthesis, in vitro, molecular docking, pharmacokinetics ADMET analysis and dynamic simulations

To investigate the therapeutic potential of 5-Fluorouracil-based analogues, a straightforward synthetic technique was employed to synthesize a novel series of 5-arylurea uracil derivatives (AUFU01-03) and aryl-urea derivatives bearing perfluorophenyl (AUPF01-03). Reliable tools such as infrared (IR), Nuclear Magnetic Resonance (NMR) spectra, and elemental analyses were utilized to confirm the chemical structures and purity of these compounds. In comparison to healthy noncancerous control skin fibroblast cells (BJ-1), we examined the antiproliferative efficacy of compounds (AUFU01-03) and (AUPF01-03) against specific human malignant cell lines of the breast (MCF-7), and colon (HCT-116). Based on the MTT experiment results, compounds AUFU03 and AUPF01-03 possessed highly cytotoxic effects. Among these, cytotoxicity was demonstrated by compounds AUPF01-03 with IC50 values (AUPF01, IC50 = 167 ± 0.57 µM, AUPF02, IC50 = 23.4 ± 0.68 µM and AUPF03, IC50 = 28.8 ± 1.13 µM, respectively, on MCF-7), relative to 5-Fluorouracil as reference drug (IC50 = 160.7 ± 0.22 µM). Compound AUPF01 showed safety on BJ-1 cells up to a concentration of 100 µM (% cytotoxicity = 3.9 ± 0.42 %), so AUPF01 was selected for further studies. At the gene, the expression levels of BCL-2 gene were decreased significantly in MCF-7 + 5-FU and reached the lowest level in MCF-7 + AUPF01. In contrast, the expression levels of pro-apoptotic genes (p53 and BAX) were increased in MCF-7 + 5-FU, and reached a significantly higher level in MCF-7 + AUPF01. Apoptosis/necrosis assays demonstrated that AUPF01 induced S and G2/M phase cell cycle arrest in MCF-7 cells. Moreover, the efficacy of these compounds against anti-cancer protein receptors was assessed using molecular docking. The results indicated that compound AUPF01 exhibited high binding energies, effectively interacting with the active sites of crucial proteins such as EGFR, CDK2, ERalfa, BAX1, BCL2, and P53. These interactions involved a diverse range of chemical bonding types, suggesting the potential of these substances to inhibit enzyme activities. Moreover, computational ADMET analyses of these compounds demonstrated compliance with Lipinski’s criteria, indicating favorable physicochemical properties. Additionally, molecular dynamics (MD) simulations revealed stable complexes of AUPF01 with EGFR, CDK2, ERalfa, BAX1, BCL2, and P53, as evidenced by (RMSD) values, RMSF values, and (SASA) values for the respective complexes.

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

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

Piperine analogues as dual inhibitors for antibacterial and antiarthritic properties through impact of ligands optimization, docking and water solvation

The prevalence of bacterial diseases poses a significant challenge because of how they can develop resistance to antibiotics and evade the human immune system, highlighting the need for novel therapeutic approaches. Bacterial infection leads to the degradation of bone tissue and the development of arthritis. This study investigates the antibacterial and antirheumatic properties of piperine analogues. Computational analyses, including molecular docking quantum chemical studies and ADMET analysis, are performed to screen out potential inhibitory compounds. A library of 100 ligands is obtained from PubChem and subjected to virtual screening using various filters, including pharmacophore properties, molecular docking, and toxicity prediction, to identify potential candidates. Four compounds, P1-P4, are selected for further investigation using quantum chemical methods. These compounds are subjected to quantum chemical spectroscopic analysis, including UV–visible and IR spectra. The molecular geometries are fully optimized. HOMO and LUMO orbitals including their energies are calculated to estimate intermolecular charge transfer properties Molecular docking results revealed “compound P3 displayed the highest binding affinity to both proteins, with binding energies of 9.0 kcal/mol and 9.8 kcal/mol for FtsZ and Neutrophil collagenase proteins, respectively”. The analysis of 2D and 3D interactions between the selected compounds and both proteins reveals the formation of three important hydrogen bonds between ligand P3 and the FtsZ protein, as well as two hydrogen bonds between P3 and the Neutrophil collagenase protein. Additionally, ligand P4 forms three hydrogen bonds with the Neutrophil collagenase protein. The small energy gap of 3.85 eV between the HOMO and LUMO of the optimized molecule Neutrophil collagenase indicates that the compound is among the category of soft compounds and biologically more active. As new insights, for the first time, we performed a comparative analysis of the energies of the docked and optimized ligands that reveal the docked ligands always possess higher energies which might be considered as energy-penalty during the docking process. This energy penalty is found to be −24, −22, −26 and −32 kcal/mol for FtsZ and −169, −40, −35 and −39 Kcal/mol for Neutrophil collagenase P1-P4, respectively. The orbital energy gap further decreases in solvation with water and increases its chemical reactivity. Under the solvation effect of water as solvent, the quantum computational results indicated enhanced molecular solubility and stability, which are critical factors for bioavailability. The researchers suggested that the combination of increased reactivity and better solubility ensures that the drug performs more effectively in biological environments, making it a more potent inhibitor for bacterial infections and arthritis. The molecular geometries including bond lengths and bond angles of all studied compounds were also influenced in a solvent environment.

Potential novel HIV-1 reverse transcriptase inhibitors: a modeling and evaluation approach

Human immunodeficiency viru (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease that severely weakens the immune system and makes patients more susceptible to infections. Although there is no definitive cure for HIV, advances in drug development offer promising prospects. In this study, we targeted HIV-1 reverse transcriptase by performing virtual screening (VS) to identify novel candidate compounds. From a database of compounds similar to the inhibitor thymidine-5'-triphosphate (TTP), three compounds (CID441663, CID123650073, and CID123789980) were selected for their docking scores, which outperformed those of the reference compound TTP (-6.2302 kcal/mol). These compounds were then subjected to ADMET, PASS, and DFT analyses. Interestingly, all three ligands showed a broad spectrum of predicted antiviral activity, including targets related to human herpes virus and HIV. Specifically, while TTP primarily targets HIV-1 reverse transcriptase, the top three ligands were predicted to target HIV-1 integrase, with CID441663 and CID123789980 displaying higher confidence in this target compared to CID123650073. These findings suggest that the candidate ligands should undergo further in vitro validation to determine their precise roles as inhibitors or antagonists, and to confirm their selective targeting of HIV-related proteins.

Potential MAO‐B Inhibitors from Cissampelos capensis L.f.: ADMET, Molecular Docking, Dynamics, and DFT Insights

This study explores the therapeutic potential of three proaporphine alkaloids—cissamaline, cissamanine, and cissamdine, which were recently isolated from Cissampelos capensis L.f., against Parkinson's disease (PD). Using computational techniques, we investigated their efficacy as inhibitors of a key protein in PD. ADMET analysis demonstrated that these alkaloids conform to the Lipinski, Pfizer, Golden Triangle, and GSK rules, indicating favorable safety, oral bioavailability, and a high probability of passing the human intestinal and blood‐brain barriers. They were neither substrates nor inhibitors of any CYP enzymes tested, indicating minimal metabolic interference and an enhanced safety profile. Molecular docking studies revealed strong binding energies with MAO‐B, PD's target. MD simulations supported these findings, showing stable interactions with MAO‐B, while Density Functional Theory (DFT) calculations highlighted the electrophilic nature of cissamanine, enhancing its potential as an effective inhibitor. These results advocate further in vitro and in vivo studies to evaluate their potential as PD therapeutics.

CXCR3-Flavonoid Interaction: A Novel Therapeutic Approach in Cancer Immunotherapy

Objective: To investigate the interactions between select flavonoids (Luteolin, Quercetin, Apigenin, Kaempferol, and Amorphine) and the CXCR3 receptor, evaluating their potential as novel therapeutic agents in cancer immunotherapy. Methods: Molecular docking simulations were employed to analyze flavonoid-CXCR3 receptor interactions. Comprehensive in silico ADMET analyses were conducted to assess pharmacokinetic properties and toxicity profiles of the compounds. Results: Flavonoids exhibited high-affinity binding to the CXCR3 receptor, with binding affinities ranging from -8.7 to -13.0 kcal/mol. Amorphine demonstrated the highest binding affinity (-13.0 kcal/mol), indicating superior inhibition potential. Luteolin showed optimal ADME characteristics, including favorable oral bioavailability (62%) and blood-brain barrier permeability (log BB -1.911). Molecular docking analyses identified critical amino acid residues (TYR205, TYR308, TRP109, PHE131, and ASN132) in flavonoid-CXCR3 interactions. In silico toxicity predictions suggested low risk profiles for all examined flavonoids. Conclusion: This study provides evidence for the potential of flavonoids as CXCR3 receptor antagonists in cancer immunotherapy. The elucidated molecular interactions and favorable ADMET profiles warrant further investigation of these compounds. Future research should focus on optimization of flavonoid-based CXCR3 inhibitors, preclinical and clinical evaluations, and assessment of their immunomodulatory effects within the tumor microenvironment. These findings contribute to the development of novel, flavonoid-derived therapeutic strategies in cancer treatment.

Anxiolytic Efficacy of Indirubin: In Vivo Approach Along with Receptor Binding Profiling and Molecular Interaction with GABAergic Pathways.

Anxiety is a natural response to stress, characterized by feelings of worry, fear, or unease. The current research was conducted to investigate the anxiolytic effect of indirubin (IND) in different behavioral paradigms in Swiss albino mice. To observe the animal's behavioural response to assess anxiolytic activity, different tests were performed, such as the open-field (square cross, grooming, and rearing), swing, dark-light, and hole cross tests. The experimental mice were administered IND (5 and 10 mg/kg, p.o.), where diazepam (DZP) and vehicle were used as positive and negative controls, respectively. In addition, a combination treatment (DZP+IND-10) was provided to the animals to determine the modulatory effect of IND on DZP. Molecular docking approach was also conducted to determine the binding energy of IND with the GABAA receptor (α2 and α3 subunits) and pharmacokinetics were also estimated. The findings revealed that IND dose-dependently significantly (p<0.05) reduced the animal's movement exerting calming behavior like DZP. IND also demonstrated the highest docking score (-7.7 kcal/mol) against the α3 subunit, while DZP showed a lower docking value (-6.4 kcal/mol) than IND. The ADMET analysis revealed that IND has proper drug-likeness and pharmacokinetic characteristics. In conclusion, IND exerted anxiolytic effects through GABAergic Pathways.

An In Silico Approach to Discover Efficient Natural Inhibitors to Tie Up Epstein–Barr Virus Infection

Epstein–Barr virus (EBV), also known as human herpesvirus 4, is a member of the herpes virus family. EBV is a widespread virus and causes infectious mononucleosis, which manifests with symptoms such as fever, fatigue, lymphadenopathy, splenomegaly, and hepatomegaly. Additionally, EBV is associated with different lymphocyte-associated non-malignant, premalignant, and malignant diseases. So far, no effective treatment or therapeutic drug is known for EBV-induced infections and diseases. This study investigated natural compounds that inhibit EBV glycoprotein L (gL) and block EBV fusion in host cells. We utilised computational approaches, including molecular docking, in silico ADMET analysis, and molecular dynamics simulation. We docked 628 natural compounds against gL and identified the four best compounds based on binding scores and pharmacokinetic properties. These four compounds, with PubChem CIDs 4835509 (CHx-HHPD-Ac), 2870247 (Cyh-GlcNAc), 21206004 (Hep-HHPD-Ac), and 51066638 (Und-GlcNAc), showed several interactions with EBV gL. However, molecular dynamics simulations indicated that the protein–ligand complexes of CID: 4835509 (CHx-HHPD-Ac) and CID: 2870247 (Cyh-GlcNAc) are more stable than those of the other two compounds. Therefore, CIDs 4835509 and 2870247 (Cyh-GlcNAc) may be potent natural inhibitors of EBV infection. These findings can open a new way for effective drug design against EBV and its associated infections and diseases.

Identification of natural compounds as potential antiviral drug candidates against Hepatitis E virus through molecular docking and dynamics simulations

Hepatitis E virus (HEV) is a single-stranded RNA virus, capable of infecting both humans and animals. This investigation targets ORF2 of HEV, as it plays an essential role in forming viral capsid. Inhibiting the capsid protein could prevent the virus from completing its life cycle and infecting new cells, making ORF2 an ideal target for new drug development, and the primary objective of this investigation is to identify the potential therapeutic candidate against HEV.The molecular docking analysis was conducted against the Hepatitis E virus ORF2 and out of the initially chosen 25 chemicals, eight demonstrated better binding affinities, particularly with Quercetin and Pinostrobin, which exhibited the most favorable binding energies. After that, theoretical ADMET analysis was analyzed to ensure the pharmacokinetics and safety profile of these therapeutic candidate. The stability of the maximum binding affinity containing compounds with the target protein was confirmed through molecular dynamics simulations over 100 ns timeframe.The finding of this investigation is highlighted as strong antiviral properties against the HEV, supported by in silico analysis, suggesting the urgent need for cost-effective and time-efficient strategies to discover potential therapeutic candidate against HEV. Further, laboratory experiments together with pre-clinical and clinical research are suggested to be carried out.