Current Issue : April-June Volume : 2025 Issue Number : 2 Articles : 5 Articles
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, disabling disorder of unknown etiology, poor prognosis, and limited therapeutic options. Previously, 35-dimaleamylbenzoic acid (35-DMBA) was shown to exert resolving effects in IPF, offering a promising alternative for treating this disease; however, the molecular mechanisms associated with this effect have not been explored. Objetive: We evaluated the potential antifibrotic mechanisms of 35-DMBA by network pharmacology (NP) and molecular docking (MD). Methods: 35-DMBA-associated targets were identified by screening in SwissTargetPrediction. IPF-associated targets were identified using lung tissue meta-analysis and public databases. Common targets were identified, and a protein–protein interaction (PPI) network was constructed; we ranked the proteins in the PPI network by topological analysis. MD validated the binding of 35-DMBA to the main therapeutic targets. Results: A total of 57 common targets were identified between 35-DMBA and IPF; caspase 8, 9, 3, and 7; myeloid leukemia-induced cell differentiation protein Mcl-1; and poly [ADP-ribose] polymerase 1 are primary targets regulating PPI networks. Functional analysis revealed that the common targets are involved in the pathological features of tissue fibrosis and primarily in the apoptotic process. MD revealed favorable interaction energies among the three main targets regulating PPI networks. Conclusions: NP results suggest that the antifibrotic effect of 35-DMBA is due to its regulation of the pathological features of IPF, mainly by modulating signaling pathways leading to apoptosis, suggesting its therapeutic potential to treat this disease....
Endolysins of bacteriophages, which degrade the bacterial cell wall peptidoglycan, are applicable in many industries to deal with biofilms and bacterial infections. While multi-domain endolysins have both enzymatically active and cell wall-binding domains, single-domain endolysins consist only of an enzymatically active domain, and their mechanism of peptidoglycan binding remains unexplored, for this is a challenging task experimentally. This research aimed to explore the binding mechanism of endolysins using computational approaches, namely molecular docking and bioinformatical tools, and analyze the performance of these approaches. The docking engine Autodock Vina 1.1.2 and the 3D-RISM module of AmberTools 24 were studied in the current work and used for receptor–ligand affinity and binding energy calculations, respectively. Two possible mechanisms of single-domain endolysin–ligand binding were predicted by Autodock Vina and verified by the 3D-RISM. As a result, the previously obtained experimental results on peptidoglycan binding of the isolated gamma phage endolysin PlyG enzymatically active domain were supported by molecular docking. Both methods predicted that single-domain endolysins are able to bind peptidoglycan, with Autodock Vina being able to give accurate numerical estimates of protein–ligand affinities and 3D-RISM providing comparative values....
Colorectal cancer ranks as the third most prevalent form of cancer on a global scale. The abnormal expression of Peroxiredoxin 1, or PRDX1, plays an important role in cancer progression and tumor cell survival. This makes inhibiting this protein a promising target for colorectal cancer treatment. In order to develop effective PRDX1 inhibitors, a drug design investigation based on computational methods was carried out using a collection of recently synthesized compounds derived from two main chemical base structures: C-5 sulfenylated amino uracils and 1,2,3-triazole benzothiazole derivatives. To obtain the PRDX1 protein PDB ID: 7WET, molecular docking was performed on the studied compounds in combination with PRDX1. The 1,2,3-triazole benzothiazole derivatives showed interesting docking results. For instance, nine promising candidates were distinguished by their formation of better stable complexes with PRDX1 in terms of E (binding) from −7.0 to −7.3 kcal/mol, namely, 7WET-L18, 7WET-L17, 7WET-L25, 7WET-L19, 7WET-L20, 7WET-L26, 7WET-L22, 7WET-L23, and 7WET-L24, as well as an E of −6.8 kcal/mol for Celastrol, a known PRDX1 inhibitor. Moreover, an extensive evaluation of ADME-TOX was performed to predict the pharmacokinetic, pharmacodynamic, and toxicological properties of the compounds studied. The findings offer significant support for the prospective application of these analogs in the fight against colorectal cancer....
Acute pancreatitis (AP), induced by tetracycline, a widely used antibiotic, poses significant clinical and toxicological challenges, yet its molecular mechanisms remain unclear. This study aims to promote drug toxicology strategies for the effective investigation of the putative toxicity and potential molecular mechanisms of antibiotic drugs through the study of tetracycline in AP. Using the SwissTargetPrediction, SEA Search, Super-PRED, GeneCards, Drugbank, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD), we identified 259 potential targets associated with tetracycline exposure and AP. Further refinement via the STRING database and Cytoscape (version 3.10.1) software highlighted 22 core targets, including TP53, TNF, and AKT1. Functional enrichment via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) identified pathways through Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, highlighting PI3K-Akt, MAPK, HIF-1, and AGE-RAGE as critical mediators in tetracycline-induced AP. Molecular docking confirmed the strong binding between tetracycline and the core targets. Overall, these findings suggest that tetracycline may affect the occurrence and progression of pancreas-related inflammation by regulating pancreatic cell apoptosis and proliferation, activating inflammatory signaling pathways, and regulating lipid metabolic pathways. This study provides a theoretical basis for understanding the molecular mechanism of tetracycline-induced AP and lays the foundation for the prevention and treatment of digestive system diseases associated with excessive exposure to tetracycline antibiotics and certain tetracyclines. In addition, our network toxicology approach has accelerated the elucidation of toxic pathways in antibiotic drugs that lack specific characteristics....
The synthesis of tetra- and pentanorlabdane compounds with rearranged cycle B based on commercially available (+)-sclareolide is reported. Desired compounds were prepared from intermediate ketones via Baeyer–Villiger oxidation. The structures of synthesized compounds were confirmed by spectral IR, 1D (1H, 13C, and DEPT), and 2D (H-COSY, H,C-HSQC, H,C-HMBC, H,NHMBC, NOESY) NMR analyses, mass-spectrometry and single crystal X-rays diffraction. Two out of the four synthesized compounds showed high antifungal and antibacterial activities comparable to and exceeding standard antifungal (caspofungin) and antibacterial (kanamycin) agents. DFT calculations show that in gas and DCM, compound 4 is more stable than 3 with a difference in the Gibbs free energy of 23.3 kJ/mol and 20.7 kJ/mol, respectively. In water and methanol, compound 3 is slightly more stable, by 2.4 kJ/mol and 2.78 kJ/mol, respectively. Molecular docking to four targets DNA gyrase from E. coli (1KZN), Fabz from P. aeruginosa (1U1Z), dihydrofolate reductase from C. albicans (3QLS) and MurB from E. coli (2Q85) showed good agreement with the results of in vitro evaluation and confirmed the biological activity of compounds 3 and 4, with binding affinities comparable and for some targets exceeding that of Caspofungin and Kanamycin....
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