Molecular docking study of anti-viral FDA-approved drugs as novel entry and replication Ebola viral inhibitors

Background & Objective: Because of the reported high ability of virulence and the lack of appropriate drug of Ebola virus during the last decades, many investigations have been accomplished regarding discovery and the introduction of anti-Ebola drugs. The aim of this research was the bioinformatical study of entry and replication of Ebola viral inhibition by drug repurposing. Materials & Methods: It is a descriptive-analytic study. In order to investigate the mode of interaction of the compounds with GP and VP40 binding sites, the chemical structures of all compounds were designed using ChemDraw program, then were transferred into Hyperchem software for energy minimization. Molecular docking simulation was accomplished using AutoDock 4.2 program. Results: Docking results revealed the hydrophobic, hydrogen bond, π-π and π-cation contacts were involved in the drug-protein interactions. Among all the studied drugs, the best docking results were related to Amodiaquine and Diphenoxylate drugs displayed. Actually, this compounds had the most negative ΔGbinding that indicated suitable modes and favorable interactions with the amino acid residues at the binding site of GP and VP40. The weakest docking results were exhibited for Dirithromycin and Erythromycin drugs due to the high hydrophilic character of them. In general, the presence of hydrophobic portions, tertiary amines, and optimal hydrogen bonds increases the strength of anti-Ebola medications. Conclusion: According to the results of the molecular docking, the entire FDA-approved drugs revealed a good inhibition effect on entry and replication Ebola vira

Identification and Introduction of Possible Inhibitors of Plasmodium Falciparum Lactate Dehydrogenase Enzyme using Computational Techniques of Drug Design and Virtual Screening based on Macromolecules

Introduction: Human malaria is an infectious-blood disease that is caused by the Plasmodium genus. Anopheles mosquitoes transmit malaria by biting and are well-known as the only biological carriers of this disease. The aim of this research was the identification and introduction of possible inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme using computational techniques of drug design and virtual screening based on macromolecule. Methods: In this analytical-descriptive study, 8733 compounds were initially collected from the PubChem database. In the second step, different filtrations were performed on the library compounds. The selected compounds showed good drug-like properties and pharmacokinetics. Finally, molecular docking simulations were carried out to investigate their binding mode and interactions in the enzyme's active site. Results: The results of the present study showed that the bonds involved in the binding of the compounds with the enzyme were hydrophobic interactions and hydrogen bonds, and the π-π interaction was in the lower priority. Among the studied compounds, the best docking results were related to the compounds with identification codes CID_23603310, CID_23603337, CID_11912187 and CID_11912184 and free binding energy of -29.10, -9.06, -9.04 and -9.00 kcal/mol, respectively. In general, lipophilic parts and hydrogen bonds increased the affinity and inhibited the enzyme. Conclusion: Based on the results, all the compounds showed suitable connections in the active site of the enzyme and can be proposed as potential effective inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme

Investigations of antiproliferative and antioxidant activity of β-lactam morpholino-1,3,5-triazine hybrids

TARAMAPUBMEDTARAMASCOPUSTARAMAWOSThis article reports for the first time the synthesis of some novel β-lactam morpholino-1,3,5-triazine hybrids by a [2+2]-cycloaddition reaction of imines 7a–c, 9a–c and 11 with ketenes derived from substituted acetic acids. The reaction was totally diastereoselective, leading exclusively to the formation of cis-β-lactams 8a–l, 10a–f and 12a–c. The synthesized compounds were tested for activity towards SW1116, MCF-7 and HepG2 cancer cell lines and non-cancerous HEK-293 cell line by MTT assay. None of the compounds exert an observable effect on HepG2, MCF-7 and HEK-293 cells, but compounds 7b, 8f, 8g, 8l, 10c, and 10e exhibited excellent growth inhibitory activity (IC50 7b > 8f > 8g. Collectively, the in vitro capabilities of some of these morpholino-triazine imines and β- lactams suggest possible applications to development of new antioxidants and DNA binding therapeutics.Şiraz Üniversitesi (96-GR-SC-23

Three-Component Synthesis of Chromeno β-Lactam Hybrids for Inflammation and Cancer Screening

International audienceHighly diastereoselective synthesis of chromeno β-lactam hybrids was achieved by an efficient one-pot three-component reaction. With this procedure, the desired β-lactam products were obtained in good yields and with exclusive cis stereoselection, by combining a variety of benzaldehydes, malononitrile, and either 5,5-dimethylcyclohexane-1,3-dione or 4-hydroxycoumarin in the presence of 1,4-diazabicyclo[2.2.2]octane under reflux conditions. These adducts were structurally characterized on the basis of IR, 1 H NMR, 13 C NMR spectral data and elemental analysis. Each of the synthesized compounds was screened for anti-inflammatory and anticancer activities. β-Lactams 5b and 8b showed a 53.4 and 19.8 anti-inflammatory ratio, respectively, and 5b appeared more active than the well-known dexamethasone corticosteroid used for the treatment of rheumatoid and skin inflammation. β-Lactams 5a, 5b, 5e, 5f, 5g, 8c, 8j and 8p also showed good antitumor activity against the SW1116 (colon cancer) cell line without notable cytotoxicity towards the HepG2 control cell line

Paclitaxel Response Can Be Predicted With Interpretable Multi-Variate Classifiers Exploiting DNA-Methylation and miRNA Data

International audienceTo address the problem of resistance to paclitaxel treatment, we have investigated to which extent is possible to predict Breast Cancer (BC) patient response to this drug. We carried out a large-scale tumor-based prediction analysis using data from the US National Cancer Institute's Genomic Data Commons. These data sets comprise the responses of BC patients to paclitaxel along with six molecular profiles of their tumors. We assessed 10 Machine Learning (ML) algorithms on each of these profiles and evaluated the resulting 60 classifiers on the same BC patients. DNA methylation and miRNA profiles were the most informative overall. In combination with these two profiles, ML algorithms selecting the smallest subset of molecular features generated the most predictive classifiers: a complexity-optimized XGBoost classifier based on CpG island methylation extracted a subset of molecular factors relevant to predict paclitaxel response (AUC = 0.74). A CpG site methylation-based Decision Tree (DT) combining only 2 of the 22,941 considered CpG sites (AUC = 0.89) and a miRNA expression-based DT employing just 4 of the 337 analyzed mature miRNAs (AUC = 0.72) reveal the molecular types associated to paclitaxel-sensitive and resistant BC tumors. A literature review shows that features selected by these three classifiers have been individually linked to the cytotoxic-drug sensitivities and prognosis of BC patients. Our work leads to several molecular signatures, unearthed from methylome and miRNome, able to anticipate to some extent which BC tumors respond or not to paclitaxel. These results may provide insights to optimize paclitaxel-therapies in clinical practice

Synthesis, docking and evaluation of in vitro anti-inflammatory activity of novel morpholine capped β-lactam derivatives

International audienceThis study reports the synthesis and biological investigation of three series of novel β-lactams bearing a morpholine substituent of the nitrogen center. These products were synthesized via Staudinger's [2+2]-ketene-imine cycloaddition reaction. The cycloadducts were fully characterized by spectral data, including 1 H-NMR, 13 C-NMR, IR, mass spectroscopy and elemental analyses, and then evaluated for anti-inflammatory activity. A number of the derivatives demonstrated higher therapeutic ratios than dexamethasone and corticosteroid medication. In silico molecular docking experiments showed a good correlation between the experimental activity and the calculated binding affinity to human inducible nitric oxide synthase, the enzymatic target for the anti-inflammatory response