Current drug discovery technologies最新文献

Objective: Increased quinolinic acid (QA) accumulation has been found in many neurodegenerative diseases. Artemisia absinthium (A. absinthium) has been reported to have neuroprotective and antioxidant activities. This study was designed to evaluate the effect of A. absinthium in QAinduced neurotoxicity in OLN-93 Cells.

Methods: OLN-93 cells were cultured in a DMEM medium containing 10% (v/v) fetal bovine serum, 100 units/ml penicillin, and 100 μg/ml streptomycin. The cells were pretreated with concentrations of A. absinthium extract for two h and then exposed to QA for 24 h. After 24 h cell viability, the level of malondialdehyde (MDA), reactive oxygen species (ROS), and apoptotic cells were quantitated in OLN-93 Cells.

Results: Pretreatment with A. absinthium extract prevented the loss of cell viability in OLN-93 cells. ROS generation, lipid peroxidation, and apoptosis in QA-injured OLN-93 cells were reduced following A. absinthium extract pretreatment.

Conclusion: A. absinthium extract exerts its neuroprotective effect against QA-induced neurotoxicity via oxidative stress and apoptosis modulation.

Aim: The prenyl-binding protein, phosphodiesterase-δ (PDEδ), is essential for the localization of prenylated KRas to the plasma membrane for its signaling in cancer.

Introduction: The general objective of this work was to develop virtually new potential inhibitors of the PDEδ protein that prevent Ras enrichment at the plasma membrane.

Methods: All computational molecular modeling studies were performed by Molecular Operating Environment (MOE). In this study, sixteen crystal structures of PDEδ in complex with fifteen different fragment inhibitors were used in the protein-ligand interaction fingerprints (PLIF) study to identify the chemical features responsible for the inhibition of the PDEδ protein. Based on these chemical characteristics, a pharmacophore with representative characteristics was obtained for screening the BindingDB database. Compounds that matched the pharmacophore model were filtered by the Lipinski filter. The ADMET properties of the compounds that passed the Lipinski filter were predicted by the Swiss ADME webserver and by the ProTox-II-Prediction of Toxicity of Chemicals web server. The selected compounds were subjected to a molecular docking study.

Results: In the PLIF study, it was shown that the fifteen inhibitors formed interactions with residues Met20, Trp32, Ile53, Cys56, Lys57, Arg61, Gln78, Val80, Glu88, Ile109, Ala11, Met117, Met118, Ile129, Thr131, and Tyr149 of the prenyl-binding pocket of PDEδ. Based on these chemical features, a pharmacophore with representative characteristics was composed of three bond acceptors, two hydrophobic elements, and one hydrogen bond donor. When the pharmacophore model was used in the virtual screening of the Binding DB database, 2532 compounds were selected. Then, the 2532 compounds were screened by the Lipinski rule filter. Among the 2532 compounds, two compounds met the Lipinski's rule. Subsequently, a comparison of the ADMET properties and the drug properties of the two compounds was performed. Finally, compound 2 was selected for molecular docking analysis and as a potential inhibitor against PDEδ.

Conclusion: The hit found by the combination of structure-based pharmacophore generation, pharmacophore- based virtual screening, and molecular docking showed interaction with key amino acids in the hydrophobic pocket of PDEδ, leading to the discovery of a novel scaffold as a potential inhibitor of PDEδ.

Background: The tyrosine kinase epidermal growth factor receptor (TK-EGFR) has recently been identified as a useful target for anticancer treatments. The major concern for current EGFR inhibitors is resistance due to mutation, which can be overcome by combining more than one pharmacophore into a single molecule.

Aim and objective: In the present study, various hybrids of 1,3,4-oxadiazole-chalcone derivatives were gauged for their EGFR inhibitory potential.

Method: The design of 1,3,4-oxadiazole-chalcone hybrid derivatives was carried out and in silico studies, viz., molecular docking, ADME, toxicity, and molecular simulation, were performed as EGFR inhibitors. Twenty-six 1,3,4-oxadiazole-chalcone hybrid derivatives were designed using the combilib tool of the V life software. AutoDock Vina software was used to perform in silico docking studies, while SwissADME and pkCSM tools were used to analyse molecules for ADME and toxicity. Desmond software was used to run the molecular simulation.

Result: Around 50% of molecules have shown better binding affinity as compared to standard and cocrystallized ligands.

Conclusion: Molecule 11 was found to be a lead molecule that has the highest binding affinity, good pharmacokinetics, good toxicity estimates and better protein-ligand stability.

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