Search Results (13)

This study aimed to provide an inclusive in silico investigation for the identification of novel drug targets that can be exploited to develop drug candidates for treating oral infections caused by S. sputigena. By coupling subtractive genomics with an in silico drug discovery approach, we identified dTDP-4-dehydrorhamnose 3,5-epimerase (UniProt ID: C9LUR0), UTP-glucose-1-phosphate uridyltransferase (UniProt ID: C9LRH1), and imidazole glycerol phosphate synthase (UniProt ID: C9LTU7) as three unique proteins crucial for the S. sputigena life cycle with no substantial similarity to human proteins. These potential drug targets served as the starting point for screening bioactive phytochemicals (1090 compounds) from the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database. Among the screened natural products, cubebin (IMPHY001912) showed a higher affinity for two of the three selected targets, as evidenced by molecular docking and molecular dynamics studies. Given its favorable drug-like profile and possible multitargeting behavior, cubebin could be further exploited as an antibacterial agent for treating S. sputigena-mediated oral infections. It is worth nothing that cubebin could be the active ingredient of appropriate formulations such as mouthwash and/or toothpaste to treat S. sputigena-induced periodontitis, with the advantage of limiting the adverse effects that could affect the use of current drugs. Full article

Snakebite envenoming is a significant health threat, particularly in tropical regions, causing substantial morbidity and mortality. Traditional treatments, including antivenom therapy, have limitations and associated risks. This research aims to discover novel phytochemical antidotes for snakebites, specifically targeting the western diamondback rattlesnake (Crotalus atrox) venom metalloproteinase Atrolysin. Utilizing pharmacoinformatic techniques such as molecular docking, high-throughput ligand screening, pharmacophore mapping, pharmacokinetic profiling, and molecular dynamics (MD) simulations, we analyzed phytochemicals from the Indian Medicinal Plants, Phytochemistry And Therapeutics (IMPPAT) database alongside well-known nine metalloproteinase inhibitors from the PubChem database. From an initial set of 17,967 compounds, 4708 unique compounds were identified for further study. These compounds were evaluated based on drug likeness, molecular descriptors, ADME properties, and toxicity profiles. Binding site predictions and molecular docking identified key interacting residues and binding energies, highlighting several promising compounds. Density functional theory (DFT) analysis provided insights into these compounds’ electronic properties and stability. MD simulations assessed the dynamic stability of protein-ligand complexes using parameters such as RMSD, RMSF, the radius of gyration, and hydrogen bond interactions. This study identified top candidates, including CID5291, IMPHY001495, IMPHY014737, IMPHY008983, IMPHY008176, and IMPHY003833, based on their favorable binding energies, interaction forces, and structural stability. These findings suggest that the selected phytochemicals have the potential to serve as effective alternatives to traditional antivenom treatments, offering a promising avenue for further research and development in snakebite management. Full article

Breast cancer progression is strongly influenced by estrogen receptor-α (ERα), a ligand-activated transcription factor that regulates hormone binding, DNA interaction, and transcriptional activation. ERα plays a key role in promoting cell proliferation in breast tissue, and its overexpression is associated with the advancement of breast cancer through estrogen-mediated signaling pathways. Targeting ERα is, therefore, a promising therapeutic strategy for breast cancer. However, there are currently no phytochemical-based drug candidates approved for effectively inhibiting breast cancer progression driven by elevated ERα expression. This study aims to identify phytochemical inhibitors from Croton bonplandianum against ERα using pharmacoinformatics approaches. Eighty-three bioactive compounds from C. bonplandianum were retrieved from the IMPPAT (Indian Medicinal Plants, Phytochemistry, and Therapeutics) database and screened through molecular docking for their binding affinity to ERα. The top candidates were further evaluated through molecular dynamics simulations, ADME analysis, toxicity assessment, and quantum mechanics-based DFT calculations. The thermodynamic properties and HOMO-LUMO energy gap values indicated that the selected compounds were both stable and active. Among them, 2,3-oxidosqualene (CID-5366020) and 5,8,11-eicosatriynoic acid, trimethylsilyl ester (CID-91696396) demonstrated the most potent inhibitory activity against ERα. These findings suggest that these compounds have significant potential as therapeutic agents for breast cancer treatment by targeting ERα. Full article

Diabetic nephropathy (DN) is a serious diabetes-related complication leading to kidney damage. Cinnamomum tamala (CT), traditionally used in managing diabetes and kidney disorders, has shown potential in treating DN, although its active compounds and mechanisms are not fully understood. This study aims to identify CT’s bioactive compounds and explore their therapeutic mechanisms in DN. Active compounds in CT were identified using the Indian Medicinal Plants, Phytochemicals and Therapeutics database, and their potential targets were predicted with PharmMapper. DN-related targets were sourced from GeneCards, and therapeutic targets were identified by intersecting the compound–target and disease–target data. Bioinformatics analyses, including the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment studies, were performed on these targets. A protein–protein interaction network was constructed using STRING and Cytoscape. Molecular docking and dynamics simulations validated the most promising compound–target interactions. Six active compounds in CT were identified, along with 347 potential therapeutic targets, of which 70 were DN-relevant. Key targets like MMP9, EGFR, and AKT1 were highlighted, and the PPAR and PI3K-AKT signaling pathways were identified as the primary mechanisms through which CT may treat DN. CT shows promise in treating DN by modulating key pathways related to cellular development, inflammation, and metabolism. Full article

(1) Background: Diabetic retinopathy (DR) is a major complication of diabetes, marked by abnormal angiogenesis, microaneurysms, and retinal hemorrhages. Traditional Ayurvedic medicine advocates multi-target strategies for DR management. However, the mechanisms by which Solanum xanthocarpum (SX) and Plumbago zeylanica (PZ) exert therapeutic effects are not well understood; (2) Methods: To investigate these mechanisms, we employed network pharmacology and molecular docking techniques. Phytochemicals from SX and PZ were identified using the IMPPAT database and Swiss Target Prediction tool. DR-related protein targets were sourced from the GeneCards database, and common targets were identified through Venn diagram analysis. STRING and Cytoscape were used to construct and analyze protein–protein interaction networks. Pathway enrichment was performed with Gene Ontology and KEGG databases; (3) Results: We identified 28 active phytoconstituents, targeting proteins such as EGFR, SRC, STAT3, AKT1, and HSP90AA1. Molecular docking and dynamics simulations confirmed the strong binding affinities of these compounds to their targets; (4) Conclusions: The study highlights the multi-target activity of SX and PZ, particularly in pathways related to EGFR tyrosine kinase inhibitor resistance and PI3K–AKT signaling. These findings provide valuable insights into their therapeutic potential for DR, suggesting the effective modulation of key molecular pathways involved in the disease. Full article

Traditional treatments of cancer have faced various challenges, including toxicity, medication resistance, and financial burdens. On the other hand, bioactive phytochemicals employed in complementary alternative medicine have recently gained interest due to their ability to control a wide range of molecular pathways while being less harmful. As a result, we used a network pharmacology approach to study the possible regulatory mechanisms of active constituents of Cordia myxa for the treatment of liver cancer (LC). Active constituents were retrieved from the IMPPAT database and the literature review, and their targets were retrieved from the STITCH and Swiss Target Prediction databases. LC-related targets were retrieved from expression datasets (GSE39791, GSE76427, GSE22058, GSE87630, and GSE112790) through gene expression omnibus (GEO). The DAVID Gene Ontology (GO) database was used to annotate target proteins, while the Kyoto Encyclopedia and Genome Database (KEGG) was used to analyze signaling pathway enrichment. STRING and Cytoscape were used to create protein–protein interaction networks (PPI), while the degree scoring algorithm of CytoHubba was used to identify hub genes. The GEPIA2 server was used for survival analysis, and PyRx was used for molecular docking analysis. Survival and network analysis revealed that five genes named heat shot protein 90 AA1 (HSP90AA1), estrogen receptor 1 (ESR1), cytochrome P450 3A4 (CYP3A4), cyclin-dependent kinase 1 (CDK1), and matrix metalloproteinase-9 (MMP9) are linked with the survival of LC patients. Finally, we conclude that four extremely active ingredients, namely cosmosiin, rosmarinic acid, quercetin, and rubinin influence the expression of HSP90AA1, which may serve as a potential therapeutic target for LC. These results were further validated by molecular dynamics simulation analysis, which predicted the complexes with highly stable dynamics. The residues of the targeted protein showed a highly stable nature except for the N-terminal domain without affecting the drug binding. An integrated network pharmacology and docking study demonstrated that C. myxa had a promising preventative effect on LC by working on cancer-related signaling pathways. Full article

The effectiveness of all antibiotics in the β-lactam group to cure bacterial infections has been impaired by the introduction of the New Delhi Metallo-β-lactamase (NDM-1) enzyme. Attempts have been made to discover a potent chemical as an inhibitor to this enzyme in order to restore the efficacy of antibiotics. However, it has been a challenging task to develop broad-spectrum inhibitors of metallo-β-lactamases. Lack of sequence homology across metallo-β-lactamases (MBLs), the rapidly evolving active site of the enzyme, and structural similarities between human enzymes and metallo-β-lactamases, are the primary causes for the difficulty in the development of these inhibitors. Therefore, it is imperative to concentrate on the discovery of an effective NDM-1 inhibitor. This study used various in silico approaches, including molecular docking and molecular dynamics simulations, to investigate the potential of phytochemicals to inhibit the NDM-1 enzyme. For this purpose, a library of about 59,000 phytochemicals was created from the literature and other databases, including FoodB, IMPPAT, and Phenol-Explorer. A physiochemical and pharmacokinetics analysis was performed to determine possible toxicity and mutagenicity of the ligands. Following the virtual screening, phytochemicals were assessed for their binding with NDM-1using docking scores, RMSD values, and other critical parameters. The docking score was determined by selecting the best conformation of the protein–ligand complex. Three phytochemicals, i.e., butein (polyphenol), monodemethylcurcumin (polyphenol), and rosmarinic acid (polyphenol) were identified as result of pharmacokinetics and molecular docking studies. Furthermore, molecular dynamics simulations were performed to determine structural stabilities of the protein–ligand complexes. Monodemethylcurcumin, butein, and rosmarinic acid were identified as potential inhibitors of NDM-1 based on their low RMSD, RMSF, hydrogen bond count, average Coulomb–Schrödinger interaction energy, and Lennard–Jones–Schrödinger interaction energy. The present investigation suggested that these phytochemicals might be promising candidates for future NDM-1 medication development to respond to antibiotic resistance. Full article

The present study investigated the antioxidant potential of aqueous methanolic extracts of Hemidesmus indicus (L.) R.Br., followed by a pharmacoinformatics-based screening of novel Keap1 protein inhibitors. Initially, the antioxidant potential of this plant extract was assessed via antioxidant assays (DPPH, ABTS radical scavenging, and FRAP). Furthermore, 69 phytocompounds in total were derived from this plant using the IMPPAT database, and their three-dimensional structures were obtained from the PubChem database. The chosen 69 phytocompounds were docked against the Kelch–Neh2 complex protein (PDB entry ID: 2flu, resolution 1.50 Å) along with the standard drug (CPUY192018). H. indicus (L.) R.Br. extract (100 µg × mL⁻¹) showed 85 ± 2.917%, 78.783 ± 0.24% of DPPH, ABTS radicals scavenging activity, and 161 ± 4 μg × mol (Fe (II)) g⁻¹ ferric ion reducing power. The three top-scored hits, namely Hemidescine (−11.30 Kcal × mol⁻¹), Beta-Amyrin (−10.00 Kcal × mol⁻¹), and Quercetin (−9.80 Kcal × mol⁻¹), were selected based on their binding affinities. MD simulation studies showed that all the protein–ligand complexes (Keap1–HEM, Keap1–BET, and Keap1–QUE) were highly stable during the entire simulation period, compared with the standard CPUY192018–Keap1 complex. Based on these findings, the three top-scored phytocompounds may be used as significant and safe Keap1 inhibitors, and could potentially be used for the treatment of oxidative-stress-induced health complications. Full article

Metabolic reprogramming is a key attribute of cancer progression. An altered expression of pyruvate kinase M2 (PKM2), a phosphotyrosine-binding protein is observed in many human cancers. PKM2 plays a vital role in metabolic reprogramming, transcription and cell cycle progression and thus is deliberated as an attractive target in anticancer drug development. The expression of PKM2 is essential for aerobic glycolysis and cell proliferation, especially in cancer cells, facilitating selective targeting of PKM2 in cell metabolism for cancer therapeutics. We have screened a virtual library of phytochemicals from the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database of Indian medicinal plants to identify potential activators of PKM2. The initial screening was carried out for the physicochemical properties of the compounds, and then structure-based molecular docking was performed to select compounds based on their binding affinity towards PKM2. Subsequently, the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties, PAINS (Pan-assay interference compounds) patterns, and PASS evaluation were carried out to find more potent hits against PKM2. Here, Tuberosin was identified from the screening process bearing appreciable binding affinity toward the PKM2-binding pocket and showed a worthy set of drug-like properties. Finally, molecular dynamics simulation for 100 ns was performed, which showed decent stability of the protein-ligand complex and relatival conformational dynamics throughout the trajectory. The study suggests that modulating PKM2 with natural compounds is an attractive approach in treating human malignancy after required validation. Full article

The 3-phosphoinositide-dependent protein kinase 1 (PDPK1) has a significant role in cancer progression and metastasis as well as other inflammatory disorders, and has been proposed as a promising therapeutic target for several malignancies. In this work, we conducted a systematic virtual screening of natural compounds from the IMPPAT database to identify possible PDPK1 inhibitors. Primarily, the Lipinski rules, ADMET, and PAINS filter were applied and then the binding affinities, docking scores, and selectivity were carried out to find effective hits against PDPK1. Finally, we identified two natural compounds, 11-Hydroxytephrosin and Torosaflavone A, bearing substantial affinity with PDPK1. Both compounds showed drug-likeness as predicted by the ADMET analysis and their physicochemical parameters. These compounds preferentially bind to the ATP-binding pocket of PDPK1 and interact with functionally significant residues. The conformational dynamics and complex stability of PDPK1 with the selected compounds were then studied using interaction analysis and molecular dynamics (MD) simulations for 100 ns. The simulation results revealed that PDPK1 forms stable docked complexes with the elucidated compounds. The findings show that the newly discovered 11-Hydroxytephrosin and Torosaflavone A bind to PDPK1 in an ATP-competitive manner, suggesting that they could one day be used as therapeutic scaffolds against PDPK1-associated diseases including cancer. Full article

Oral squamous cell carcinoma (OSCC) is a major cause of death in developing countries because of high tobacco consumption. RAC-alpha serine-threonine kinase (AKT1) is considered as an attractive drug target because its prolonged activation and overexpression are associated with cancer progression and metastasis. In addition, several AKT1 inhibitors are being developed to control OSCC and other associated forms of cancers. We performed a screening of the IMPPAT (Indian Medicinal Plants, Phytochemistry and Therapeutics) database to discover promising AKT1 inhibitors which pass through various important filters such as ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, physicochemical properties, PAINS (pan-assay interference compounds) filters, PASS (prediction of activity spectra for substances) analysis, and specific interactions with AKT1. Molecules bearing admirable binding affinity and specificity towards AKT1 were selected for further analysis. Initially, we identified 30 natural compounds bearing appreciable affinity and specific interaction with AKT1. Finally, tuberosin and villosol were selected as potent and selective AKT1 inhibitors. To obtain deeper insights into binding mechanism and selectivity, we performed an all-atom molecular dynamics (MD) simulation and principal component analysis (PCA). We observed that both tuberosin and villosol strongly bind to AKT1, and their complexes were stable throughout the simulation trajectories. Our in-depth structure analysis suggested that tuberosin and villosol could be further exploited in the therapeutic targeting of OSCC and other cancers after further clinical validations. Full article

Tyrosine-protein kinase Yes (YES1) belongs to the Tyrosine-protein kinase family and is involved in several biological activities, including cell survival, cell–cell adhesion, cell differentiation, and cytoskeleton remodeling. It is highly expressed in esophageal, lung, and bladder cancers, and thus considered as an attractive drug target for cancer therapy. In this study, we performed a virtual screening of phytoconstituents from the IMPPAT database to identify potential inhibitors of YES1. Initially, the molecules were retrieved on their physicochemical properties following the Lipinski rule of five. Then binding affinities calculation, PAINS filter, ADMET, and PASS analyses followed by an interaction analysis to select safe and clinically better hits. Finally, two compounds, Glabrene and Lupinisoflavone C (LIC), with appreciable affinities and a specific interaction towards the AlphaFold predicted structure of YES1, were identified. Their time-evolution analyses were carried out using an all-atom molecular dynamics (MD) simulation, principal component analysis, and free energy landscapes. Altogether, we propose that Glabrene and LIC can be further explored in clinical settings to develop anticancer therapeutics targeting YES1 kinase. Full article

Casein kinase-1 alpha (CK1α) is a multifunctional protein kinase that belongs to the serine/threonine kinases of the CK1α family. It is involved in various signaling pathways associated with chromosome segregation, cell metabolism, cell cycle progression, apoptosis, autophagy, etc. It has been known to involve in the progression of many diseases, including cancer, neurodegeneration, obesity, and behavioral disorders. The elevated expression of CK1α in diseased conditions facilitates its selective targeting for therapeutic management. Here, we have performed virtual screening of phytoconstituents from the IMPPAT database seeking potential inhibitors of CK1α. First, a cluster of compounds was retrieved based on physicochemical parameters following Lipinski’s rules and PAINS filter. Further, high-affinity hits against CK1α were obtained based on their binding affinity score. Furthermore, the ADMET, PAINS, and PASS evaluation was carried out to select more potent hits. Finally, following the interaction analysis, we elucidated three phytoconstituents, Semiglabrinol, Curcusone_A, and Liriodenine, posturing considerable affinity and specificity towards the CK1α binding pocket. The result was further evaluated by molecular dynamics (MD) simulations, dynamical cross-correlation matrix (DCCM), and principal components analysis (PCA), which revealed that binding of the selected compounds, especially Semiglabrinol, stabilizes CK1α and leads to fewer conformational fluctuations. The MM-PBSA analysis suggested an appreciable binding affinity of all three compounds toward CK1α. Full article