Molecular docking studies, DFT, and ADMET calculations of some flavonoids and their characteristic structural features involved in inhibition of pro-inflammatory enzymes.

Inflammation is an immune system response triggered by pathogens, damaged cells, or stimuli. Some regulatory enzymes, such as phosphodiesterase, hyaluronidase, collagenase, and lipoxygenase, play an essential role in the inflammatory process. Polyphenolic compounds, such as flavonoids, are active suppressors of inflammatory cytokines, modulators of transcription factors, and inflammation-related pathways. A set of flavonoid structures was screened and docked against inflammation pathway enzymes. Amentoflavone has been shown to cause interactions with phosphodiesterase enzymes, while Bilobetin and Silibinin demonstrated an increase in binding energy with collagenase enzymes. The retrieved compounds from the docking study were subjected to DFT theory. The results showed that the LUMO orbital is located on the flavonoid part. The thermochemical parameters indicated that Silibinin is more stable than other compounds. The ADMET profile predicted that Silibinin can be used orally among the compounds. Silibinin can be introduced as a promising anti-inflammatory agent demonstrating phosphodiesterase and collagenase inhibitory properties.

6-Bromo quinazoline derivatives as cytotoxic agents: design, synthesis, molecular docking and MD simulation.

Based on unselectively, several side effects and drug resistance of available anticancer agents, the development and research for novel anticancer agents is necessary. In this study, a new series of quinazoline-4(3H)-one derivatives having a thiol group at position 2 of the quinazoline ring (8a-8 h) were designed and synthesized as potential anticancer agents. The Chemical structures of all compounds were characterized by 1H-NMR, 13C-NMR, and Mass spectroscopy. The antiproliferative activity of all derivatives were determined against two cancer cell lines (MCF-7 and SW480) and one normal cell lines (MRC-5) by the MTT method. Cisplatin, Erlotinib and Doxorubicin were used as positive controls. The results of in vitro screening showed that 8a with an aliphatic linker to SH group was the most potent compound with IC50 values of 15.85 ± 3.32 and 17.85 ± 0.92 µM against MCF-7 and SW480 cell lines, respectively. 8a indicated significantly better potency compared to Erlotinib in the MCF-7 cell line. The cytotoxic results obtained from testing compound 8a on the normal cell line, revealing an IC50 value of 84.20 ± 1.72 µM, provide compelling evidence of its selectivity in distinguishing between tumorigenic and non-tumorigenic cell lines. Structure-activity relationship indicated that the variation in the anticancer activities of quinazoline-4(3H)-one derivatives was affected by different substitutions on the SH position. Molecular docking and MD simulation were carried out for consideration of the binding affinity of compounds against EGFR and EGFR-mutated. The binding energy of compounds 8a and 8c were calculated at -6.7 and - 5.3 kcal.mol- 1, respectively. Compounds 8a and 8c were found to establish hydrogen bonds and some other important interactions with key residue. The DFT analysis was also performed at the B3LYP/6-31 + G(d, p) level for compounds 8a, 8c and Erlotinib. Compound 8a was thermodynamically more stable than 8c. Also, the calculated theoretical and experimental data for the IR spectrum were in agreement. The obtained results delineated that the 8a can be considered an appropriate pharmacophore to develop as an anti-proliferative agent.

A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor.

DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand-protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.

Synthesis, design, biological evaluation, and computational analysis of some novel uracil-azole derivatives as cytotoxic agents.

The design and synthesis of novel cytotoxic agents is still an interesting topic for medicinal chemistry researchers due to the unwanted side effects of anticancer drugs. In this study, a novel series of uracil-azole hybrids were designed and synthesized. The cytotoxic activity, along with computational studies: molecular docking, molecular dynamic simulation, density functional theory, and ADME properties were also, evaluated. The compounds were synthesized by using 3-methyl-6-chlorouracil as the starting material. Cytotoxicity was determined using MTT assay in the breast carcinoma cell line (MCF-7) and Hepatocellular carcinoma cell line (HEPG-2). These derivatives demonstrated powerful inhibitory activity against breast and hepatocellular carcinoma cell lines in comparison to Cisplatin as positive control. Among these compounds, 4j displayed the best selectivity profile and good activity with IC50 values of 16.18 ± 1.02 and 7.56 ± 5.28 µM against MCF-7 and HEPG-2 cell lines respectively. Structure-activity relationships revealed that the variation in the cytotoxic potency of the synthesized compounds was affected by various substitutions of benzyl moiety. The docking output showed that 4j bind well in the active site of EGFR and formed a stable complex with the EGFR protein. DFT was used to investigate the reactivity descriptors of 4a and 4j. The outputs demonstrated that these uracil-azole hybrids can be considered as potential cytotoxic agents.

Design, synthesis, computational study and cytotoxic evaluation of some new quinazoline derivatives containing pyrimidine moiety.

Quinazoline derivatives, as an important category of heterocyclic compounds, have received much attention for the design and development of new drugs due to their various pharmacological properties. Besides, there is a great deal of evidence showing pyrimidine analogs as anticancer agents. Thus, in the present study, for the design of new target compounds with cytotoxic activity, we focused on various quinazolinone and pyrimidine hybrids. A new series of quinazoline-pyrimidine hybrid derivatives (6a-6n) have been designed and synthesized as novel antiproliferative agents. All the synthesized compounds characterized based on their IR, NMR and Mass spectroscopic data. Antiproliferative activities of the new compounds were evaluated against three human cancer cell lines (MCF-7, A549, SW-480). The compounds were found to have appropriate potential with IC50 values ranging from 2.3 ± 5.91 to 176.5 ± 0.7 µM against the tested cell lines. Compound 6n exerted the highest antiproliferative activity with IC50 values of 5.9 ± 1.69 µM, 2.3 ± 5.91 µM and 5.65 ± 2.33 µM against A549, SW-480 and MCF-7 respectively. The results indicated that 6n could induce apoptosis in A549 cell line in a dose dependent manner and arrest in the S phase of cell cycle. Docking studies were also done to investigate the detailed binding pattern of the synthesized compounds against EGFR. Furthermore, molecular dynamic simulation and binding free energy calculation have been done to rescore initial docking pose of the synthesized compounds using ensemble-based MMGB/PBSA free energy method. According to the results, free energy calculation confirmed biological activity of compounds and also, Arg 817 and Lys 721 residues had the pivotal role in the high potency of 6n. Finally, the drug likeness and in silico ADME study were also predicted.

6-Bromoquinazoline Derivatives as Potent Anticancer Agents: Synthesis, Cytotoxic Evaluation, and Computational Studies.

A series of 6-bromoquinazoline derivatives (5a-j) were synthesized. Cytotoxic effectiveness of compounds was done against two cancerous cell lines (MCF-7 and SW480) by standard MTT method. Fortunately, all of the compounds showed desirable activity in reducing the viability of the studied cancerous cell lines with IC50 value in the range of 0.53-46.6 µM. Compound 5b with a fluoro substitution at meta position of the phenyl moiety showed stronger activity than cisplatin with IC50 =0.53-1.95 µM. Studies on the hit compound (5b) through apoptosis assay illustrated that it could induce apoptosis in MCF-7 cell lines in dose dependent manner. Molecular docking study was done to investigate the detailed binding modes and interactions with EGFR as a plausible mechanism. The drug- likeness was predicted. To survey the reactivity of compounds, DFT calculation was performed. Taken together, 6-bromoquinazoline derivatives, especially 5b can be considered as hit compounds to rational drug designing as antiproliferative agents.

Design, synthesis and evaluation of novel 1,2,4-triazole derivatives as promising anticancer agents.

Herein, we reported the synthesis of nineteen novel 1,2,4-triazole derivatives including 1,3-diphenyl-2-(1H-1,2,4-triazol-1-yl) propan-1-ones (7a-e), 1-(1,3-diphenylpropan-2-yl)-1H-1,2,4-triazole (8a-c) and 1,4-diphenyl-2-(1H-1,2,4-triazol-1-yl) butane-1,4-diones (10a-k). The structures of these derivatives were confirmed by spectroscopic techniques like IR, 1H-NMR, Mass spectroscopy and Elemental analysis. The cytotoxic activities of the synthesized compounds were evaluated against three human cancer cell lines including MCF-7, Hela and A549 using MTT assay. Compounds 7d, 7e, 10a and 10d showed a promising cytotoxic activity lower than 12 µM against Hela cell line. The safety of these compounds was also, evaluated on MRC-5 as a normal cell line and relieved that most of the synthesized compounds have proper selectivity against normal and cytotoxic cancerous cell lines. Finally, molecular docking studies were also, done to understand the mechanism and binding modes of these derivatives in the binding pocket of aromatase enzyme as a possible target.

Synthesis, biological evaluation, and computational studies of some novel quinazoline derivatives as anticancer agents.

A series of quinazolinone derivatives (7a-7h) were synthesized as antiproliferative agents. All compounds, were synthesized through three steps method and structurally evaluated by FTIR, 1H-NMR, 13CNMR and Mass spectroscopy. Their cytotoxic activities were assessed using MTT protocol against three humans cancerous (MCF-7, A549 and 5637) and normal (MRC-5) cell lines. In addition, molecular docking and simulation studies of the synthesized compounds were performed to assessment their orientation, interaction mode against EGFR as plausible mechanism of quinazoline compounds as anticancer agents. The synthesized compounds mostly showed moderate activity against the three studied cell lines. They also indicated an appropriate selectivity against tumorigenic and non-tumorigenic cell line. The molecular docking results also confirmed biological activity. Most of the compounds fulfilled Lipinski rule. Collectively, these compounds with further modification can be considered as potent antiproliferative agents.

Quinazoline analogues as cytotoxic agents; QSAR, docking, and in silico studies.

BACKGROUND AND PURPOSE: Synthesis and investigation of pharmacological activity of novel compounds are time and money-consuming. However, computational techniques, docking, and in silico studies have facilitated drug discovery research to design pharmacologically effective compounds. EXPERIMENTAL APPROACH: In this study, a series of quinazoline derivatives were applied to quantitative structure-activity relationship (QSAR) analysis. A collection of chemometric methods were conducted to provide relations between structural features and cytotoxic activity of a variety of quinazoline derivatives against breast cancer cell line. An in silico-screening was accomplished and new impressive lead compounds were designed to target the epidermal growth factor receptor (EGFR)-active site based on a new structural pattern. Molecular docking was performed to delve into the interactions, free binding energy, and molecular binding mode of the compounds against the EGFR target. FINDINGS/RESULTS: A comparison between different methods significantly indicated that genetic algorithm-partial least-squares were selected as the best model for quinazoline derivatives. In the current study, constitutional, functional, chemical, resource description framework, 2D autocorrelation, and charge descriptors were considered as significant parameters for the prediction of anticancer activity of quinazoline derivatives. In silico screening was employed to discover new compounds with good potential as anticancer agents and suggested to be synthesized. Also, the binding energy of docking simulation showed desired correlation with QSAR and experimental data. CONCLUSION AND IMPLICATIONS: The results showed good accordance between binding energy and QSAR results. Compounds Q1-Q30 are desired to be synthesized and applied to in vitro evaluation.

Educational video to improve CPAP use in patients with obstructive sleep apnoea at risk for poor adherence: a randomised controlled trial.

BACKGROUND: Suboptimal adherence to CPAP limits its clinical effectiveness in patients with obstructive sleep apnoea (OSA). Although rigorous behavioural interventions improve CPAP adherence, their labour-intensive nature has limited widespread implementation. Moreover, these interventions have not been tested in patients at risk of poor CPAP adherence. Our objective was to determine whether an educational video will improve CPAP adherence in patients at risk of poor CPAP adherence. METHODS: Patients referred by clinicians without sleep medicine expertise to an urban sleep laboratory that serves predominantly minority population were randomised to view an educational video about OSA and CPAP therapy before the polysomnogram, or to usual care. The primary outcome was CPAP adherence during the first 30 days of therapy. Secondary outcomes were show rates to sleep clinic (attended appointment) and 30-day CPAP adherence after the sleep clinic visit date. RESULTS: A total of 212 patients met the eligibility criteria and were randomised to video education (n=99) or to usual care (n=113). There were no differences in CPAP adherence at 30 days (3.3, 95% CI 2.8 to 3.8 hours/day video education; vs 3.5, 95% CI 3.1 to 4.0 hours/day usual care; p=0.44) or during the 30 days after sleep clinic visit. Sleep clinic show rate was 54% in the video education group and 59% in the usual care group (p=0.41). CPAP adherence, however, significantly worsened in patients who did not show up to the sleep clinic. CONCLUSIONS: In patients at risk for poor CPAP adherence, an educational video did not improve CPAP adherence or show rates to sleep clinic compared with usual care. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02553694.

X-linked agammaglobulinemia: a survey of 33 Iranian patients.

In order to determine the clinical and laboratory features of X-linked agammaglobulinemia, the records of 33 male patients with XLA were reviewed during 22 years (1980-2002) in the Iranian referral center of primary immunodeficiency disorders. The patients' ages ranged from 20 to 360 months (median 113 months). The median age at the onset of the disease was 8 months and the median age of diagnosis was 48 months, with a median diagnosis delay of 33 months. Almost all of the patients presented common infectious diseases, which were: pneumonia, otitis, diarrhea, sinusitis, and arthritis. During the course of illness, infections in the respiratory tract, gastrointestinal tract, central nervous system, and musculoskeletal system were seen in 93.9%, 75.8%, 33.3%, and 21.2% of XLA patients, respectively. The most common complications of these patients were chronic infections in 75.8% of them, including: chronic otitis media, chronic sinusitis, chronic diarrhea, and bronchiectasis.