Background: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses an enormous challenge to human health and economy at a global level. According to WHO's latest data, till now, there have been a total of 641,435,884 confirmed cases of COVID-19, and the associated deaths are 6,621,060. Though few vaccinations have been approved for emergency usage, antiviral medications for long-term therapeutics are still being sought. The current research seeks to identify the inhibitory effect of iminosugars, particularly 1-deoxynojirmycin (IDNJ) series, against SARS-CoV-2 main protease (SARS-CoV2-Mpro) using an inhibitor optimization approach for 1DNJ series.
Aim: The aim of this study was to investigate the inhibitory effect of iminosugars, specifically 1-deoxynojirmycin (1-DNJ) derivatives, on SARS-CoV-2 main protease (Mpro) as it plays a vital role in viral propagation and transcription and is shaped like a heart.
Objective: The main objective of this study was to find the possibility of 1-DNJ derivatives being potent inhibitors against SARS CoV2 Mpro. This study was focused on finding the most probable conformation in which DNJ derivatives could bind to Mpro. Another objective was to obtain molecular-level details by getting insights into stable interactions formed between the ligand and receptor.
Method: In silico molecular mechanics (MM) based techniques were employed to identify the best-docked inhibitors using molecular docking, and complexes that showed stable interactions were further subjected to 200 ns of molecular dynamics (MD) simulations to check the stability of ligand into the binding pocket of SARS-CoV2-Mpro. The inhibitors that formed stable complexes were further tested for their ADME properties in order to check the pharmacokinetic parameters as well as their therapeutic importance.
Result: Docking was performed on 29 compounds from two different series against SARS-CoV-2 main protease, Mpro (PDB ID: 6LZE). Twelve compounds were found to have high docking scores and better interactions with the active site of Mpro, as compared to the co-crystallized ligand. Furthermore, the three highest-scoring docked compounds (17a, 7, and 8) depicted strong and stable complex formation, throughout the 200 ns molecular dynamics simulation, by analyzing the binding energy (MM/GBSA). The molecules were discovered to form stable interactions with conserved active-site residues, which play an important role in demonstrating activity in structure-based drug design. The ADMET analysis was performed using Qikprop, and the proposed stable derivatives passed all of the needed drug discovery standards, potentially inhibiting the Mpro of SARS-CoV-2.
Conclusion: The present findings confer opportunities for compounds 17a, 7, and 8 that could be developed as new therapeutic agents against COVID-19. These compounds are
Background: Rhizoma drynariae, a classic prescription in traditional Chinese medicine, has long been used for the treatment of osteonecrosis of the femoral head (ONFH), but its potential targets and molecular mechanisms remain to be further explored.
Objective: This study aims to explore the mechanism of Rhizoma drynariae in ONFH treatment via network pharmacology and in vitro experiments.
Methods: Targets of Rhizoma drynariae and ONFH were predicted using relevant databases, and intersection analysis was conducted to screen for shared targets. A PPI network of the shared targets was built using STRING to identify the key targets. Functional enrichment analyses of Gene Ontology and KEGG pathway data were carried out using R software. The compound-target-pathway network was constructed for Rhizoma Drynariae in the treatment with ONFH using Cytoscape 3.9.0. Cell proliferation was assessed using CCK8 and apoptosis was detected using (Propidium Iodide) PI staining and western blotting.
Results: This study depicts the interrelationship of the bioactive compounds of Rhizoma drynariae with ONFH-associated signaling pathways and target receptors and is a potential reagent for ONFH treatment.
Conclusion: Based on a network pharmacology analysis and in vitro experiment, we predicted and validated the active compounds and potential targets of Rhizoma drynariae, provide valuable evidence of Rhizoma Drynariae in future ONFH treatment.
Aim: To provide new methods and ideas for the clinical application of integrated traditional Chinese and Western medicine in the treatment of esophageal cancer.
Background: Traditional Chinese medicine compound Kushen injection (CKI) has been widely used in the clinic with adjuvant radiotherapy and chemotherapy. However, the mechanism of action of CKI as adjuvant therapy for esophageal cancer has not yet been described.
Methods: This study is based on network pharmacology, data mining, and molecular docking technology to explore the mechanism of action of CKI in the treatment of esophageal cancer. We obtained the effective ingredients and targets of CKI from the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) and esophageal cancer-related genes from the Online Mendelian Inheritance in Man (OMIM) and GeneCards databases.
Results: CKI mainly contains 58 active components. Among them, the top 5 active ingredients are quercetin, luteolin, naringenin, formononetin, and beta-sitostero. The target protein of the active ingredient was matched with the genes associated with esophageal cancer. The active ingredients targeted 187 esophageal cancer target proteins, including AKT1, MAPK1, MAPK3, TP53, HSP90AA1, and other proteins. Then, we enriched and analyzed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) and used AutoDockVina to dock the core targets and compounds. Finally, PyMOL and Ligplot were used for data visualization.
Conclusion: This study provides a new method and ideas for the clinical application of integrated traditional Chinese and Western medicine in the treatment of esophageal cancer.
Background: Buyang Huanwu Decoction (BHD) is used to regulate blood circulation and clear collaterals and is widely used in coronary heart disease. However, the active compounds and the mechanism of BHD used to treat restenosis are less understood.
Objective: The study aimed to explore the potential mechanism of Buyang Huanwu decoction BHD for the treatment of restenosis using network pharmacology and molecular docking experiments.
Methods: The bioactive components of BHD and their corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Encyclopaedia of Traditional Chinese Medicine (ETCM) databases as well as literature. Restenosisassociated therapeutic genes were identified from the OMIM, Drugbank, GEO, and Dis- GeNET databases. Genes related to the vascular smooth muscle cell (VSMC) phenotype were obtained from the gene ontology (GO) database and literature. The core target genes for the drug-disease-VSMC phenotype were identified using the Venn tool and Cytoscape software. Moreover, the "drug-component-target-pathway" network was constructed and analyzed, and pathway enrichment analysis was performed. The connection between the main active components and core targets was analyzed using the AutoDock tool, and PyMOL was used to visualize the results.
Results: The "compound-target-disease" network included 80 active ingredients and 599 overlapping targets. Among the bioactive components, quercetin, ligustrazine, ligustilide, hydroxysafflor yellow A, and dihydrocapsaicin had high degree values, and the core targets included TP53, MYC, APP, UBC, JUN, EP300, TGFB1, UBB, SP1, MAPK1, SMAD2, CTNNB1, FOXO3, PIN1, EGR1, TCF4, FOS, SMAD3, and CREBBP. A total of 365 items were obtained from the GO functional enrichment analysis (p < 0.05), whereas the enrichment analysis of the KEGG pathway identified 30 signaling pathways (p < 0.05), which involved the TGF-β signaling pathway, Wnt signaling pathway, TRAF6-mediated induction of NF-κB and MAPK pathway, TLR7/8 cascade, and others. The molecular docking results revealed quercetin, luteolin, and ligustilide to have good affinity with the core targets MYC and TP53.
Conclusion: The active ingredients in BHD might act on TP53, MYC, APP, UBC, JUN, and other targets through its active components (such as quercetin, ligustrazine, ligustilide, hydroxysafflor yellow A, and dihydrocapsaicin). This action of BHD may be transmitted via the involvement of multiple signaling pathways, including the TGF-β signaling pathway, Wnt signaling pathway, TRAF6-mediated induction of NF-κB and MAPK pathway, and TLR7/8 cascade, to treat restenosis by inhibiting the phenotype switching and proliferation of VSMC.
Background: The compounds containing heterocyclic cores with O, N and/or S atoms are bioactive and valuable molecules in the field of drug discovery and development. There are several applications in different areas for the molecules having oxadiazole moiety in their structures viz. herbicides and corrosion inhibitors, electron-transport materials, polymers and luminescent materials. Hence, demand for new anticonvulsant, antibacterial and analgesic agents has turned into an imperative assignment in the area of medicinal chemistry to improve therapeutic efficacy as well as safety.
Methods: In the journey of new anticonvulsive, antibacterial and analgesic molecules with better potency, some newer Oxadiazole analogues were attained by a sequence of synthetic steps with the substituted acrylic acids. IR and 1H-NMR spectral data were used for the structure elucidation of obtained chemical compounds. In this perspective, the anticonvulsant, antibacterial and analgesic activities were evaluated for synthetically obtained newer chemical moieties. Furthermore, a molecular docking study was performed to elucidate the binding modes of synthesized ligands in the active pockets of Cox-1/2 enzymes, DNA Gyrase and GABA inhibitors.
Results: It has been observed that all the synthetic molecules showed good analgesic activity while A1 molecule demonstrated better analgesic activity. In the case of anticonvulsant and antibacterial activity among other ligands, C1 molecule possessed profound anticonvulsant activity whereas B1 molecule showed maximum antibacterial activity and molecular docking study also endorsed the same consequences.
Conclusion: It might be recognized from the present study that prepared compounds are distinctive in lieu of their structure and noticeable biological activity. In the quest for a newer group of anticonvulsant, antibacterial and analgesic molecules, these compounds might be useful for the society.
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