RESUMEN
Protein tyrosine phosphatase 1B (PTP1B) has been identified as a promising drug target for the development of diabetes medications via an inhibition mechanism. Using a computational approach, this study investigates the binding mechanism of lead optimized natural compounds from Allium sativum against the human PTP1B. The molecular docking, induced-fit docking, and binding free energy calculations were analyzed using Schrödinger Suite 2021-2. MD simulation, and gene enrichment analysis was achieved via the Desmond module of Schrödinger to identify best compounds as inhibitors against PTP1B in diabetes management. The docking scores of the lead optimized compounds were good; 5280443_121 from apigenin had the best binding score of -9.345 kcal/mol, followed by 5280443_129 with a binding score of -9.200 kcal/mol, and 5280863_177 from kaempferol had a binding score of -8.528 kcal/mol, followed by 5280863_462 with a binding score of -8.338 kcal/mol. The top two lead optimized compounds, docked better than the standard PTP1B inhibitor (-7.155 kcal/mol), suggesting them as potent inhibitors than the standard PTP1B inhibitor. The outcomes of the induced-fit docking were consistent with the increased binding affinity used in the Glide computation of the five conformed poses between the derivatives (5280443_121, 5280443_129, 5280863_177, and 5280863_462) and the protein (PTP1B). Based on the binding fee energies (MM-GBSA), the lead optimized compounds from kaempferol exhibited more stability than those from apigenin. In the pharmacophore development, all the models exhibit good results across the different metrics. The best performing model with five of five matches on a 1.34 and 1.33 phase score was DDRRR_1, DDRRR_2, and DDDRR_1. The average BEDROC value (= 160.9) was 1, while the average EF 1% value across all models was 101. There were no substantial conformational modifications during the MD simulation process, indicating that the apigenin derivatives (5280443_121) was stable in the protein's active site in 100 ns. IGF1R, EGFR, INSR, PTPN1, SRC, JAK2, GRB2, BCAR1, and IRS1 are among the 11 potential targets found in the protein-protein interaction (PPI) of A. sativum against PTP1B that may be important in A. sativum's defense against PTP1B. Sixty-four (64) pathways were found by KEGG pathway enrichment analysis to be potentially involved in the anti-PTP1B of A. sativum. Consequently, data obtained indicates the effectiveness of the in silico studies in identifying potential lead compounds in A. sativum against PTP1B target.Communicated by Ramaswamy H. Sarma.
RESUMEN
Background: We aimed in this article to assess the likeliness of efavirenz to induce functional senescence in Drosophila melanogaster (fruit fly). Methods: Ten different concentrations of EFV were mixed with fly food and fed to 3-day-old flies orally for a 7 day LC50 calculation. Drug concentrations from LC50 were selected for a 28 day survival to determine the duration of treatment for behavioral and biochemical assays. A 5day feeding plan was used to investigate the effects of the drug on organismal, neuromuscular, reproductive, and metabolic senescence. An in silico study was executed to decipher a molecular interaction of Drosophila enzymes glutathione-s-transferase (GST) or acetylcholinesterase (AChE) with EFV. Results: The calculated LC50 of EFV was 118 mg/10-g fly diet. The test drug induced a significant (P < 0.05) increase in fly mortality, climbing difficulty, and procreative deficits after a 5 day oral exposure. Similarly, there were significant (P < 0.05) biochemical alterations, which suggested in vivo biochemical damage against total thiols (T-SH), SOD (superoxide dismutase), CAT (catalase), GST, AChE, and MDA (malondialdehyde) in the test flies compared to the control groups. In silico study revealed a significantly (P < 0.05) higher binding energy between EFV and the active amino acids of fly AChE and GST when compared to the substrates or standard inhibitors respectively. Conclusion: EFV exhibited ecotoxic potentials evidenced by age-related deficits in the fly's functional integrity such as sluggish movement, procreative deficiency, increased mortality, and oxidant-antioxidant inequality. Results from in silico study suggested antagonism against GST and AChE activities as a likely mechanism of EFV-induced toxicity in the fruit fly.
RESUMEN
BACKGROUND: Globally, head and neck cancer is the sixth most common cancer. Despite the advancement in treatment, drug resistance remains a major cause for setback. In an earlier work, the authors reported that Boswellia dalzielii (Hutch) stem bark exhibited dose-dependent cytotoxicity in head and neck cancer cells, AW8507. Therefore, the cell death induction effect of Boswellia dalzielii stem bark chloroform extract in head and neck cancer cell line, AW8507, and its derived constituent on cell cycle and apoptosis proteins was further investigated. METHODS: The cell death induction activity of the Boswellia dalzielii stem bark chloroform fraction (CLBD) in AW8507 was determined using Annexin V-FITC/PI staining in flow cytometry. High-performance liquid chromatography-mass spectrometry was employed for compounds analysis of the CLBD, and reverse virtual screening was used to identify the mechanism of action of the compound, acetyl-11-keto-beta-boswellic acid, that was elucidated in the Boswellia dalzielii chloroform fraction. RESULTS: The data obtained showed that Boswellia dalzielii stem bark Chloroform extract increased the percentage of cells presenting for early apoptosis from 4.14 to 10.10% in AW8507 cells. High-performance liquid chromatography-mass spectrometry analysis of the chloroform fraction identified acetyl-11-keto-beta-boswellic acid. Reverse virtual screening on selected proteins showed that acetyl-11-keto-beta-boswellic acid is a multi-protein target compound. It binds preferably to phosphorylated-cyclin dependent kinase 1 (p-CDK1) (binding score = - 9.2 kcal/mol), blocking the activation of cyclin B-CDK1 needed for cell cycle progression at G2/M phase of the cell cycle. Acetyl-11-keto-beta-boswellic acid also binds more tightly with αß tubulin (binding score = 8.9 kcal/mol) than with the standard drug, docetaxel (binding score = 8.3 kcal/mol). CONCLUSIONS: The results obtained confirmed the culpability of Boswellia dalzielii-derived acetyl-11-keto-beta-boswellic acid in the obstruction of the cell cycle progression in head and neck cancer cell line, AW8507; and the induction of apoptosis earlier reported for Boswellia dalzielii (Hutch) stem bark. Additional in vitro and/or in vivo studies would be required to validate in silico observations.
