Current computer-aided drug design最新文献

Introduction: Butyrylcholinesterase (BChE) plays a pivotal role in the progression of Alzheimer's disease. Empirical research demonstrated a fundamental alteration in the role of BChE concerning the reduction of cholinergic neurotransmission within the brains of individuals at advanced stages of Alzheimer's.

Method: This study focuses on developing potent inhibitors for Butyrylcholinesterase (BChE) in the context of Alzheimer's disease (AD) treatment. Building upon previous research, a series of 44 aromatic tertiary amine-based compounds was investigated. Starting with ADME-Tox studies, the pharmacokinetic and pharmacodynamic properties of the compounds were analyzed to select promising candidates for BChE inhibition, which is a crucial factor in AD pathology.

Results: Molecular docking analyses identified compound M18 as the most promising candidate, and further compounds (X9 and X10) were proposed based on M18's chemical structure. These compounds displayed superior properties in terms of binding energies and hydrogen bonds in comparison to M18.

Conclusion: The Molecular Dynamics (MD) simulations, which are over a 500 ns timeframe, confirmed the conformational stability of compounds X9 and X10, compared to M18. Overall, the stated results suggest that the proposed compounds, including X9 and X10 specifically, have a significant potential as candidates for BChE inhibition. This presents a promising avenue for therapeutic intervention in Alzheimer's disease.

Background: MicroRNA-584-5p (miR-584-5p) plays an important role in certain types of cancer. However, its precise role in head and neck squamous cell carcinoma (HNSC) remains unknown.

Objective: Our aim was to investigate how miR-584-5p influences HNSC.

Methods: The Cancer Genome Atlas (TCGA) provided samples for the study. We use statistical methods to evaluate the diagnostic value, the prognostic value, and the correlation with the clinical features of miR-584-5p. We analyze the target genes and the regulatory network of miR- 584-5p. Quantitative reverse transcriptase PCR (qRT-PCR) confirmed the expression of miR- 584-5p in HNSC cell lines.

Results: MiR-584-5p expression of miR-584-5p varied significantly among different types of cancer. A notable correlation was observed between elevated miR-584-5p expression and gender (p < 0.001) and histological grade (p < 0.001). Furthermore, high levels of miR-584-5p were found to be associated with a decrease in overall survival (HR: 1.44; 95% CI: 1.10-1.88; p = 0.007), progression-free survival (HR: 1.35; 95% CI: 1.02-1.79; p = 0.035) and disease-specific survival (HR: 1.54; 95% CI: 1.09-2.18; p = 0.016) in the context of HNSC. miR-584-5p demonstrated independent prognostic significance in HNSC and potentially contributes to disease progression through multiple pathways, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In particular, HNSC cell lines exhibited a substantial upregulation of miR-584-5p compared to normal epithelial cells.

Conclusions: It is possible that miR-584-5p could serve as a promising patent for a therapeutic target and prognostic biomarker for people with HNSC.

Background: Non-Alcoholic Fatty Liver Disease (NAFLD) has become a significant health and economic burden globally. Yinchenhao decoction (YCHD) is a traditional Chinese medicine formula that has been validated to exert therapeutic effects on NAFLD.

Object: The current study aimed to explore the pharmacological mechanisms of YCHD on NAFLD and further identify the potential active compounds acting on the main targets.

Methods: Compounds in YCHD were screened and collected from TCMSP and published studies, and their corresponding targets were obtained from the SWISS and SEA databases. NAFLD-related targets were searched in the GeneCards and DisGeNet databases. The "compound- intersection target" network was constructed to recognize the key compounds. Moreover, a PPI network was constructed to identify potential targets. GO and KEGG analyses were performed to enrich the functional information of the intersection targets. Then, molecular docking was used to identify the most promising compounds and targets. Finally, molecular dynamics (MD) simulations were performed to verify the binding affinity of the most potential compounds with the key targets.

Results: A total of 53 compounds and 556 corresponding drug targets were collected. Moreover, 2684 NAFLD-related targets were obtained, and 201 intersection targets were identified. Biological processes, including the apoptotic process, inflammatory response, xenobiotic metabolic process, and regulation of MAP kinase activity, were closely related to the treatment of NAFLD. Metabolic pathways, non-alcoholic fatty liver disease, the MAPK signaling pathway, and the PI3K-Akt signaling pathway were found to be the key pathways. Molecular docking showed that quercetin and isorhamnetin were the potential active compounds, while AKT1, IL1B, and PPARG were the most promising targets. MD simulations further verified that the binding of PPARG-isorhamnetin (-35.96 ± 1.64 kcal/mol) and AKT1-quercetin (-31.47 ± 1.49 kcal/mol) was due to their lowest binding free energy.

Conclusion: This study demonstrated that YCHD exerts therapeutic effects for the treatment of NAFLD through multiple targets and pathways, providing a theoretical basis for further pharmacological research on the potential mechanisms of YCHD in NAFLD.

Background: The incidence of CRC has increased worldwide over the past decade. The statistics report from WHO highlights the increased severity and fatality rate of CRC among the populations. Wnt/β-catenin is recognized as the resource for cell regeneration and cancer signaling pathways driven by frizzled receptor cofactors. Aberrant regulation of Wnt/β- catenin suppression is an important challenge in treating CRC management.

Aims and objective: The SFRP1 comprises a cysteine-rich region that is homologous to the putative Wnt-binding sites of Frizzled proteins, with the potential to impede and alter the cascade of Wnt signaling. Indirect regulation, like targeting Wnt antagonist SFRP1, is an alternative strategy to suppress the cancer signals by enhancing the apoptotic activity. Hence, this study aimed to approach the SFRP1 protein as a therapeutic target to inhibit Wnt signaling in colorectal cancer. Further, it aimed to identify the lead compounds against the SFRP1 protein, which inhibit the oncogenic expression of CRC, which might be possible using computational approaches, recognizing the importance of the SFRP1 protein role in CRC.

Methods: The homology-modeled SFRP1 structure was refined, and virtual screening was performed against the anti-cancer drugs and natural drug databases to find the best hit molecules. The molecular docking, MD, and MMGBSA analysis confirmed the firm binding of SFRP1 complexes to identify the potent CRC inhibitors.

Results: The amino acid residues Arg5, Arg11, Ala13, Lys 245, Lys274, Phe147, Pro99, and Ser277 are essential for ligand binding and show similar interactions for SFRP1 complexes. The ADME/T profile for top hits is acceptable in range and obtains the drug-likeness property. The 100ns run for MD simulation confirms the stability of protein complexes.

Conclusion: Overall, the findings of this study reveal that the lead compounds screened are capable of inhibiting SFRP1 against CRC. Targeting SFRP1 paves the way for new platforms in the field of cancer and the therapeutic sector for new approachable finds.

Background: Marine sediment bacteria have been generating considerable attention lately due to their potential as valuable reservoirs of novel antimicrobial agents.

Aim: In vitro and in silico antibacterial activities of antibacterial compounds isolated from the marine sediment bacterium Enterococcus Lactis (S-2).

Methods: Coastal sediment samples were collected from Rameswaram, Ramnathapuram District, Tamil Nadu, India. Bacteria were isolated using the crowded plate method, and their phenotypic and genotypic characteristics were studied. Purified bacteria were cultured in large volumes, secondary metabolites were extracted, and novel antibacterial agents were isolated from the aqueous extract. Novel compound antibacterial activity was studied through in-silico and invitro. The mechanism activity of antibacterial activity was confirmed by a high-resolution transmission electron microscope.

Results: Genotypic analysis confirmed that the isolated S-2 bacteria were Enterococcus lactis, and the aqueous extract showed antibacterial activity against Staphylococcus aureus (17 mm zone of inhibition) and Proteus mirabilis (12 mm zone of inhibition). A bioactive molecule, 13- hydroxy-9-(1-hydroxyethyl)-11-methoxy-2,4dioxapentacyclo[10.7.1.0³,⁴.0⁵,²¹.0¹³,¹⁶]icosa- 1(20),5,7,12,14(19), 16-hexane-18-one, was isolated from aqueous extracts of the S-2 bacterium. Chromatography and spectroscopic analysis confirmed the identity of the isolated compound. Novel compound potential antibacterial activity showing against S. aureus (18 mm zone of inhibition) and MIC 250 μg/mL, which was confirmed by tetrazolium staining. The antibacterial activity mechanism was confirmed by transmission electron microscopy. Molecular docking studies show good binding (-9.9 kcal/mol) of the compound with 3U2D, while molecular dynamic simulation studies confirm the conformationally stable structure of the complex between 3U2D and 13-hydroxy-9-(1-hydroxyethyl)-11-methoxy-2,4-dioxapentacyclo [10.7.1.0³,⁴.0⁵,²¹.0¹³,¹⁶]icosa-1(20),5,7,12,14(19), 16-hexane-18-one. It has been observed from the docking study of 3U2D with standard drug ciprofloxacin that the lower affinity is compared to the test ligand, which has a docking score of 7.3 kcal/mol. Out of interacting residues of protein 3U2D residue, Thr173 and Ile86 formed conventional hydrogen bonds.

Conclusion: Marine bacterium E. lactis produces a novel antibacterial compound (13-hydroxy- 9-(1-hydroxyethyl)-11-methoxy-2,4-dioxapentacyclo[10.7.1.0³,⁴.0⁵,²¹.0¹³,¹⁶]icosa- 1(20),5,7,12,14(19),16-hexane-18-one), which shows antibacterial activity against clinical S. aureus, confirmed by in vitro and in silico analysis. This molecule can used as a lead molecule for antibacterial activity.

Background: Virtual screening (VS) could select possible effective candidates from a large number of organic compounds, which plays an important role in network pharmacology. Virtual screening is a very important step in network pharmacology.

Objective: The accuracy of screening compounds directly determines the subsequent network construction, target determination and pathway analysis. In order to improve the accuracy of screening the important compounds in herbs for treating diabetes, a novel methodology based on complex-valued flexible neural tree (CVFNT) model and negative sample selection algorithm is presented.

Methods: In our method, diabetes-related targets were obtained by literature search. According to diabetes-related targets, active compounds were searched from the public database. The negative sample selection algorithm based on Tanimoto index was proposed to establish inactive compound set. The CVFNT model optimized was utilized to screen effective candidate compounds.

Result: Our proposed method performs better than eight classical classifiers in terms of TPR, FPR, Precision, Specificity, F1, AUC and ROC curve. Our method could also predict 18 compounds from Liangxue Sanyu Decoction, which are involved in the treatment of diabetes.

Background: Estrogen alpha has been recognized as a perilous factor in breast cancer cell proliferation and has been proficiently treated in breast cancer chemotherapy with the development of selective estrogen receptor modulators (SERMs).

Objectives: The major aim of this study was to identify the potential inhibitors against the most influential target ERα receptor by in silico studies of 115 phytochemicals from 17 medicinal plants using in silico molecular docking studies.

Methods: The molecular docking investigation was carried out by a genetic algorithm using the Auto Dock Vina program, and the validation of docking was also performed using molecular dynamic (MD) simulation by the Desmond tool of Schrödinger molecular modeling. The ADME( T) studies were performed by SWISS ADME and ProTox-II.

Results: The top ten highest binding energy phytochemicals identified were amyrin acetate (- 10.7 kcal/mol), uscharine (-10.5 kcal/mol), voruscharin (-10.0 kcal/mol), cyclitols (-10.0 kcal/mol), taraxeryl acetate (-9.9 kcal/mol), amyrin (-9.9 kcal/mol), barringtogenol C (-9.9 kcal/mol), calactin (-9.9 kcal/mol), 3-beta taraxerol (-9.8 kcal/mol), and calotoxin (-9.8 kcal/mol). A molecular docking study revealed that these phytochemical constituents showed higher binding affinity compared to the reference standard tamoxifen (-6.6 kcal/mol) towards the target protein ERα. The results of MD studies showed that all four tested compounds possess comparatively stable ligand-protein complexes with ERα target as compared to the tamoxifen- ERα complex.

Conclusion: Among the ten compounds, phytochemical amyrin acetate (triterpenoids) formed a more stable complex as well as exhibited greater binding affinity than standard tamoxifen. ADMET studies for the top ten phytochemicals showed a good safety profile. Additionally, these compounds are being reported for the first time in this study as possible inhibitors of ERα for the treatment of breast cancer by adopting the concept of drug repurposing. Hence, these phytochemicals can be further studied and can be used as a parent core molecule to develop novel lead molecules for breast cancer therapy.

Background: The clinical use of doxorubicin (DOX), an anthracycline antibiotic with broad-spectrum applications against various malignant tumors, is limited by doxorubicininduced cardiotoxicity (DIC). Eriodictyol (ERD) has shown cardioprotective effects, but the mechanism of its protective effect on DIC remains unknown.

Aims: This study aimed to explore the potential mechanisms by which ERD confers protection against DIC.

Methods: ERD and DIC targets were identified from the TCMSP, PharmMaper, SwissTargetPrediction, TargetNet, BATMAN, GeneCards, and PharmGKB databases. Differential gene expression data between DIC and normal tissues were extracted from the GEO database. A protein‒ protein interaction (PPI) network of the intersecting ERD-DIC targets was constructed using the STRING platform and visualized with Cytoscape 3.10.0 software. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for ERD-DIC cross-targets were conducted. Validation included molecular docking with AutoDock Tools software and molecular dynamics simulations with Gromacs 2019.6 software.

Results: Network pharmacology analysis revealed 43 intersecting ERD-DIC targets, including 6 key targets. GO functional enrichment analysis indicated that the intersecting targets were enriched in 550 biological processes, 45 cell components, and 41 molecular functions. KEGG pathway enrichment analysis identified 114 enriched signaling pathways. Molecular docking revealed a strong binding affinity between ERD and 6 key targets, as well as multiple targets within the ROS pathway. Molecular dynamics simulations indicated that ERD has favorable binding with 3 crucial targets.

Conclusion: The systematic network pharmacology analysis suggests that ERD may mitigate DIC through multiple targets and pathways, with the ROS pathway potentially playing a crucial role. These findings provide a reference for foundational research and clinical applications of ERD in treating DIC.

A malignant tumor is a frequent and common disease that severely threatens human health. Many mechanisms, such as cell signaling pathway, anti-apoptosis mechanism, cell stemness, metabolism, and cell phenotype, have been studied to explain the reasons for chemotherapy, radioresistance, and tumor recurrences in antitumor treatment. Cancer stem cells (CSCs) are important tumor cell subclasses that can potentially organize and regulate stem cell properties. Growing evidence suggests that CSCs can initiate tumors and constitute a significant factor in metastasis, recurrence, and treatment resistance. The inability to completely target and remove CSCs is a considerable obstacle in tumor treatment. Therefore, drugs and therapeutic strategies that can effectively intervene with CSCs are essential for the treatment of different tumor types. However, the current strategies and efficacy of targeted elimination of CSCs are very limited. Oxidative stress has been recognized to play a crucial role in cancer pathophysiology. Moreover, reactive oxygen species (ROS) production and imbalance of the built-in cellular antioxidant defense system are hallmarks of tumor and cancer etiology. The current paper will focus on the regulation and mechanism behind oxidative stress in tumors and cancer stem cells and its tumor therapy applications. Additionally, the article discusses the role of CSCs in causing tumor treatment resistance and recurrence based on a redox perspective. The study also emphasizes that targeted modulation of oxidative stress in CSCs has great potential in tumor therapy, providing novel prospects for tumor therapy.

Background: One of the most important targets in cancer immunotherapy is programmed cell death ligand 1 (PD-L1). Monoclonal antibodies developed for this target have disadvantages due to their low bioavailability and some immune-related adverse effects. Additionally, small molecules targeting PD-L1 are still in the experimental stage. At this point, discovering non-toxic natural compounds that directly or indirectly target PD-L1 is essential. In this in silico study, a comprehensive literature search was conducted to identify publications reporting the master regulator of PD-L1, which was suggested as a Signal Transducer and Activator of Transcription 3 (STAT3). The relationship between STAT3 and PD-L1 was further investigated through bioinformatic analysis.

Method: Subsequently, natural compounds targeting PD-L1 and STAT3 were screened, and compounds with suitable toxicity profiles were docked against both PD-L1 and STAT3. Following molecular docking, the selected molecules underwent DNA docking, ADMET profile analysis, and in silico assessment of biological activities. The relationship between PD-L1 and STAT3 was determined in 52 out of the 453 articles, and it was further demonstrated in genegene interactions. Following the virtual screening, 76 natural compounds were identified, and after pre-filtering based on physicochemical properties, drug-likeness, and ADMET profiles, 29 compounds remained.

Result: Subsequent docking revealed that two compounds, 6-Prenylapigenin, and Gelomulide J, persisted. ADMET and biological activity prediction results suggested that 6-Prenylapigenin is non-toxic and has the potential to inhibit PD-L1 and STAT3 in silico. The present study highlights that STAT3 serves as the master regulator of PD-L1, and it further suggests that 6- Prenylapigenin exhibits the potential to modulate PD-L1 and/or STAT3.

Conclusion: This finding could pave the way for the development of small molecules designed to block the PD-1/PD-L1 interaction by silencing the PD-L1 and/or STAT3 genes or reducing protein levels.