In silico pharmacology最新文献

Gastric and duodenal ulcers are increasingly becoming global health burdens. The side effects of conventional treatments such as non-steroid anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), antibiotics, and cytoprotective agents have necessitated the search for new medications. Plants are a rich source of active metabolites and herbal medicines have been used in the treatment of ulcers and cancers. In this study, we used in silico methods like molecular docking and MM-GBSA calculations to evaluate the effects of some anti-ulcer and anti-inflammatory phytochemicals on some key enzymes, cyclooxygenase (COX), and lipoxygenase (LOX), which are implicated in the protection and destruction of the gastric mucosa. The phytochemicals were retrieved from the literature and docked toward the binding sites of the three enzymes (COX-1, COX-2, and 5-LOX). Five compounds, rhamnetin, kaempferol, rutin, rosmarinic acid, and chlorogenic acid were observed to putatively bind to cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LOX) but not to cyclooxygenase 1 (COX-1). The interaction mechanisms between these phytochemicals and the target proteins are discussed. The compounds' drug metabolism, pharmacokinetics, and toxicity have been evaluated to assess their suitability as potential next-generation anti-ulcer and anti-inflammatory drugs.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00269-2.

Background: Diabetes Mellitus (DM) is a complex metabolic disorder with increasing global prevalence, necessitating the exploration of novel therapeutic strategies. Cyprus rotundus, a medicinal plant with a long history of traditional use, has shown promising potential in managing DM.

Aim of the study: This study aims to elucidate the mechanism of action of active components of C. rotundus in managing DM using a combination of network pharmacology and molecular docking approaches.

Materials and methods: The active compounds of C. rotundus were identified through IMPPAT and CHEBI database mining. Subsequently, compound-target are taken from swiss target prediction and SEA. Collection of DM-related targets is done through DisGeNET and TTD database. After identifying both the targets, common targets were evaluated through venny 2.1.0. by constructing venn diagram. To elucidate the potential targets of these compounds, a protein-protein interaction network was constructed by utilizing STRING database. Through network analysis, we identified key targets and pathways involved in the pathogenesis of DM and targeted by the active components of C. rotundus. Furthermore, molecular docking was performed to explore the binding affinity and interactions between the active compounds and their target proteins.

Results: This, reveal that the 12 active components of C. rotundus exert their therapeutic effects on DM through multiple mechanisms, there are 141 common target genes between C. rotundus and DM. Enrichment of the KEGG pathway mainly involves in the AGE-RAGE signaling pathway in diabetic complications, Type II DM pathway. Top 10 genes were regulated by C. rotundus in DM, including MMP9, PTGS2, CASP3, CD4, EGFR, STAT3, PPARG, AKT1, NFKB1 and MAPK3. Molecular docking analysis further validates the strong binding affinity between the active compounds and their target proteins, providing insights into their mode of action at the molecular level.

Conclusions: This study provides a systematic understanding of the mechanism of action of C. rotundus in managing DM, offering a basis for further experimental validation and drug development.

This study was to identify the molecular pathways that may explain sulforaphane's Alzheimer's disease (AD) benefits using multiple advanced in silico approaches. We found that sulforaphane regulates 45 targets, including TNF, INS, and BCL2. Therefore, it may help treat AD by reducing neuroinflammation, insulin resistance, and apoptosis. The important relationships were co-expression and pathways. 45 targets were linked to the midbrain, metabolite interconversion enzymes, 14q23.3 and 1q31.1 chromosomes, and modified residues. "Amyloid precursor protein catabolic process", "regulation of apoptotic signaling pathway", and "positive regulation of nitric oxide biosynthetic process" were the main pathways, while NFKB1, SP1, RELA, hsa-miR-17-5p, hsa-miR-16-5p, and hsa-miR-26b-5p were transcription factors and miRNAs implicated in sulforaphane In AD treatment, miRNA sponges, dexibuprofen, and sulforaphane may be effective. Furthermore, its unique physicochemical, pharmacokinetic, and biological qualities make sulforaphane an effective AD treatment, including efficient gastrointestinal absorption, drug-like properties, absence of CYP450 enzyme inhibition, not being a substrate for P-glycoprotein, ability to cross the blood-brain barrier, glutathione S-transferase substrate, immunostimulant effects, and antagonistic neurotransmitter effects. Sulforaphane is a promising compound for AD management. Further work is needed to elucidate its therapeutic effects based on our findings, including genes, miRNAs, molecular pathways, and transcription factors.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00267-4.

Escherichia coli (E. coli), a common human gut bacterium, is generally harmless but capable of causing infections and contributing to diseases like urinary tract infections, sepsis/meningitis, or diarrheal diseases. Notably, E. coli is implicated in developing gallbladder cancer (GBC) either through ascending infection from the gastrointestinal tract or via hematogenous spread. Certain E. coli strains are known to produce toxins, such as cytolethal distending toxins (CDTs), that directly contribute to the genetic mutations and cellular abnormalities observed in GBC. Broccoli (Brassica oleracea) is known for its health-promoting properties, including antimicrobial, antioxidant, and immunomodulatory effects, and is rich in essential compounds. Our study investigates the potential of the phytochemicals of B. oleracea to inhibit the CdtB (PDB ID: 2F1N) protein of E. coli which plays a significant role in the pathogenesis of GBC. By employing in silico molecular docking, Glucosinolates and Indole-3-carbinol emerged as promising inhibitors, demonstrating strong bonding affinities of -8.95 and - 8.5 Kcal/mol, respectively. The molecular dynamic simulation showed that both compounds maintained stable interaction with CdtB with minimal conformational changes observed in the protein-ligand complexes. Additionally, the ADMET analysis provided evidence for the drug-likeness properties of the lead compounds. Furthermore, the DFT (Density Functional Theory) revealed that Indole-3-carbinol is more chemically stable but less reactive than Glucosinolates, with HOMO-LUMO gaps of 5.14 eV and 4.50 eV, respectively. Finally, the in vitro antibacterial assessment confirmed the inhibitory effect of Glucosinolates and Indole-3-carbinol against E. coli through disc diffusion assay with the zone of inhibition 34.25 ± 0.541 and 28.67 ± 0.376 mm compared to the control ciprofloxacin. Our study provides crucial data for developing novel therapeutic agents targeting E. coli-associated GBC from the phytochemicals of B. oleracea.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00276-3.

Microorganisms are evolving to withstand the effect of antimicrobial agents and thereby pose a global threat known as antimicrobial resistance. Resistance towards multiple drugs due to various intrinsic as well environmental factors leads to an even more dangerous drug resistance property known as multi-drug resistance (MDR). WHO has recognized MDR bacteria as a top global threat as they complicate the treatment and augment mortality and morbidity risks. Gram-negative bacteria produce beta-lactamase enzymes that can hydrolyze beta-lactam antibiotics, impacting drug susceptibility. Stenotrophomonas maltophilia, an opportunistic pathogen, exemplifies MDR due to the production of two types of beta-lactamases. The metallo-beta-lactamase (MBL) L1 produced by the bacteria is a class B1 zinc-dependent MBL that is broadly substrate-specific and is a challenge to the currently available treatment options. This study constructs and analyzes a protein-protein interaction network of L1 beta-lactamase to comprehend its role in the MDR property of the bacteria. The network encompasses 51 proteins including L1 MBL (Smlt2667) and 382 interactions, revealing key players in MDR and potential drug targets. The network analysis aids the discernment of antimicrobial gene impact on cellular function, informing drug discovery strategies. This research addresses the emerging challenge of antibiotic resistance and identifies pathways for therapeutic intervention.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00270-9.

Antibiotic resistance in bacteria leads to high mortality rates and healthcare costs, a significant concern for public health. A colonizer of the human respiratory system, Stenotrophomonas maltophilia is frequently associated with hospital-acquired infections in individuals with cystic fibrosis, cancer, and other chronic illnesses. The importance of this study is underscored by its capacity to meet the critical demand for effective preventive strategies against this pathogen, particularly among susceptible groups of cystic fibrosis and those undergoing cancer treatment. In this study, we engineered a multi-epitope vaccine targeting S. maltophilia through genomic analysis, reverse vaccination strategies, and immunoinformatic techniques by examining a total of 81 complete genomes of S. maltophilia strains. Our investigation revealed 1945 core protein-coding genes alongside their corresponding proteomic sequences, with 191 of these genes predicted to exhibit virulence characteristics. Out of the filtered proteins, three best antigenic proteins were selected for epitope prediction while seven epitopes each from CTL, HTL, and B cell were chosen for vaccine development. The vaccine was refined and validated, showing highly antigenic and desirable physicochemical features. Molecular docking assessments revealed stable binding with TLR-4. Molecular dynamic simulation demonstrated stable dynamics with minor alterations. The originality of this investigation is rooted in the thorough techniques aimed at designing a vaccine that directly targets S. maltophilia, a microorganism of considerable clinical relevance that currently lacks an available vaccine. This study not only responds to a pressing public health crisis but also lays the groundwork for subsequent research endeavors focused on the prevention of S. maltophilia outbreaks. Further evidence from studies in mice models is needed to confirm immune protection against S. maltophilia.

Due to the high toxicity, poor efficacy and resistance associated with current anti-breast cancer drugs, there's growing interest in natural products (NPs) for their potential anti-cancer properties. Computational modelling of NPs to identify key structural features can aid in developing novel natural inhibitors. In this study, we developed statistically significant QSAR models based on NPs from the NPACT database, which have shown potential anticancer activity against the MCF-7 cancer cell lines. All the developed QSAR models were statistically robust, meeting both internal (R ²  = 0.666-0.669, R ² _adj  = 0.657-0.660, Q ² _Loo  = 0.636-0.638) and external (Q ² F _n  = 0.686-0.714, CCC _ext = 0.830-0.847) validation criteria. Consequently, they were utilized to virtually screen a series of NPs from the COCONUT database in the search for novel natural inhibitors. Molecular docking studies were conducted on the identified compounds against the human HER2 protein (PDB ID: 3PP0), which is a crucial target in breast cancer. Molecular docking analysis demonstrated that compounds 4608 and 2710 achieved the highest docking scores, with CDOCKER interaction energies of -72.67 kcal/mol and - 72.63 kcal/mol respectively. Compounds 4608 and 2710 were identified as the most promising candidates upon performing triplicate 100 ns MD simulation study using the CHARMM36 force field. DFT studies was performed to evaluate their stability and reactivity as potential drug molecules. This research contributes to the development of new natural inhibitors for breast cancer.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00266-5.

Parkinson's disease, a neurodegenerative disorder, is quickly progressing and accounts for 15% of dementia cases. Parkinson's disease is the second most frequent form of neuronal degeneration after Alzheimer's, with an average age of 55 years for individuals exhibiting neuropsychiatric and physiological symptoms. Due to the effectiveness, low toxicity, and low side effects, bioactive compounds from plants have received increased attention recently as therapeutic drugs. In the current study, effective anti-neurodegenerative phytochemicals from Dodonaea viscosa were screened using in silico methods and have been proposed to be further investigated for the treatment of Parkinson's disease. The structures of twenty bioactive chemicals were screened and graph theoretical network analysis revealed alpha-synuclein as a potent therapeutic target. Based on docking scores, an effective bioactive molecule was selected, and its energy values, electrostatic potential surface and drug-like qualities were examined using molecular orbitals, pharmacokinetics and toxicity studies. Pinocembrin was found as a superior binder based on molecular docking as it demonstrated stronger binding with - 10.2 kcal/mol. An investigation using Ramachandran plot validated the protein-ligand complex secondary structure's stability. Pinocembrin, a bioactive phytochemical from Dodonaea viscosa, may be a viable lead molecule that may be developed as a candidate medicine for anti-neurodegenerative therapy against Parkinson's disease.

Mucormycosis is a concerning invasive fungal infection with difficult diagnosis, high mortality rates, and limited treatment options. Iron availability is crucial for fungal growth that causes this disease. This study aimed to computationally target iron uptake proteins in Rhizopus arrhizus, Lichtheimia corymbifera, and Mucor circinelloides to identify inhibitors, thereby halting fungal growth and intervening in mucormycosis pathogenesis. Seven important iron uptake proteins were identified, modeled, and validated using Ramachandran plots. An in-house antifungal library of ~ 15,401 compounds was screened in molecular docking studies with these proteins. The best small molecule-protein complexes were simulated at 100 ns using Maestro, Schrodinger. Toxicity predictions suggested all six molecules, identified as the best binding compounds to seven proteins, belonged to lower toxicity levels per GHS classification. A molecular mechanics GBSA study for all seven complexes indicated low standard deviations after calculating free binding energies every 10 ns of the 100 ns trajectory. Density functional theory via quantum mechanics approaches highlighted the HOMO, LUMO, and other properties of the six best-bound molecules, revealing their binding capabilities and behaviour. This study sheds light on the molecular mechanisms and protein-ligand interactions, providing a multi-dimensional view towards the use of FDBD01920, FDBD01923, and FDBD01848 as stable antifungal ligands.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-024-00264-7.

Farnesol is a natural acyclic sesquiterpene alcohol, found in various essential oils such as, lemon grass, citronella, tuberose, neroli, and musk. It has a molecular mass of 222.372 g/mol and chemical formula of C₁₅H₂₆O. The main objective of this study was to assess the effect of farnesol on mTOR and its two downstream effectors, p70S6K and eIF4E, which are implicated in the development of cancer, via molecular dynamic simulation, and docking analysis in an in silico study. A multilayer, primarily computer-based analysis was conducted to assess farnesol's anticancer potential, with a focus on primary cancer targets. From the calculations performed, farnesol showed a binding affinity of - 9.66 kcal/mol, followed by binding affinity of - 7.4 kcal/mol and - 7.8 kcal/mol for mTOR, p70S6K and eIF4E respectively. Rapamycin showed the binding affinity of - 10.45 kcal/mol for mTOR, for p70S6K and eIF4E the calculated binding affinity was - 10.65 kcal/mol and 8.16 kcal/mol respectively. The binding affinity of farnesol was comparable to the standard drug rapamycin indicating its potential as an mTOR inhibitor. Molecular dynamics simulations suggest that the ligands (farnesol and rapamycin) were well trapped within the active site of the protein over a time gap of 50 ns. It is clear that farnesol showed relatively stable MD simulation results, with minor fluctuations and maintains a consistent binding orientation, suggesting a strong and stable interaction with the target proteins when compared to simulation data of standard drug. This study explores the potential of farnesol as an anticancer agent through an in-silico approach, focusing on its interaction with mTOR and its downstream effectors. Inhibition of mTOR signaling pathway may be responsible for the anticancer effect of farnesol. As this pathway plays a crucial role in cell proliferation and survival, making it a significant target in cancer research.