New azole derivatives showing antimicrobial effects and their mechanism of antifungal activity by molecular modeling studies

Doğan, İnci Selin; Saraç, Selma; Sarı, Suat; Kart, Didem; Gökhan, Şebnem Eşsiz; Vural, İmran; Dalkara, Sevim

doi:10.1016/j.ejmech.2017.02.035

Cited by 55 publications

(41 citation statements)

References 53 publications

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“…Unfortunately, fungal CYP51 proteins are membrane bound, making it more difficult to study their structural and biophysical characteristics . Thus, molecular modeling of the CYP51 structure has been used to explain possible protein‐fungicide interactions . This type of analysis can indicate which residues are important during ligand binding.…”

Section: Introductionmentioning

confidence: 99%

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The Y137H mutation in the cytochrome P450 FgCYP51B protein confers reduced sensitivity to tebuconazole in Fusarium graminearum

Qian

Chi

et al. 2018

Pest Management Science

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Section: Introductionmentioning

confidence: 99%

“…30 Thus, molecular modeling of the CYP51 structure has been used to explain possible protein-fungicide interactions. 31 This type of analysis can indicate which residues are important during ligand binding. First, the homology model based on the crystal structure of Aspergillus fumigatus was developed.…”

Section: Introductionmentioning

confidence: 99%

The Y137H mutation in the cytochrome P450 FgCYP51B protein confers reduced sensitivity to tebuconazole in Fusarium graminearum

Qian

Chi

et al. 2018

Pest Management Science

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“…CYP51 is one of the key enzymes of sterol biosynthesis in different biological kingdoms and serves the metabolic function such as membrane permeability, membrane fluidity, enzyme activity, cell morphology, and cell cycle progression [7][8][9]. This enzyme is found in all eukaryotes (including humans) and because the azoles interact also with other cytochrome P450-dependent enzymes (CYP3A4), a selective inhibition of the enzyme is essential for an increased therapeutic index [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Molecular Docking Studies, and Antifungal Activity Evaluation of New Benzimidazole-Triazoles as Potential Lanosterol 14α-Demethylase Inhibitors

Can

Çevik

Sağlık

et al. 2017

Journal of Chemistry

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Due to anticandidal importance of azole compounds, a new series of benzimidazole-triazole derivatives ( a-s) were designed and synthesized as ergosterol inhibitors. The chemical structures of the target compounds were characterized by spectroscopic methods. The final compounds were screened for antifungal activity against Candida glabrata (ATCC 90030), Candida krusei (ATCC 6258), Candida parapsilosis (ATCC 22019), and Candida albicans (ATCC 24433). Compounds i and s exhibited significant inhibitory activity against Candida strains with MIC 50 values ranging from 0.78 to 1.56 g/mL. Cytotoxicity results revealed that IC 50 values of compounds i and s against NIH/3T3 are significantly higher than their MIC 50 values. Effect of the compounds i and s against ergosterol biosynthesis was determined by LC-MS-MS analysis. Both compounds caused a significant decrease in the ergosterol level. The molecular docking studies were performed to investigate the interaction modes between the compounds and active site of lanosterol 14--demethylase (CYP51), which is as a target enzyme for anticandidal azoles. Theoretical ADME predictions were also calculated for final compounds.

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“…According to the binding modes obtained from several software and algorithms, the azole ring placed close to the heme and Fe 2+ , the 4‐chlorobenzene fit in the cleft surrounded by Gly303, Ile304, and Met306 making hydrophobic contacts, and the tail groups interacted with residues that form the active site gorge, for example, Tyr118, Leu376, His377, Ser378, Phe380, Met508, and Val509 (Figure ). Most of these residues were found to be important for CACYP51 inhibition according to the in vitro mutagenesis studies (Morio, Loge, Besse, Hennequin, & Le Pape, ) as well as molecular modeling studies with previously reported CACYP51 homology models (Dogan et al., ; Flowers, Colon, Whaley, Schuler, & Rogers, ; Hoekstra et al., ; Iman & Davood, ; Sheng et al., ).…”

Section: Resultsmentioning

confidence: 94%

Antifungal screening and in silico mechanistic studies of an in‐house azole library

et al. 2019

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Systemic Candida infections pose a serious public health problem with high morbidity and mortality. C. albicans is the major pathogen identified in candidiasis; however, non‐albicans Candida spp. with antifungal resistance are now more prevalent. Azoles are first‐choice antifungal drugs for candidiasis; however, they are ineffective for certain infections caused by the resistant strains. Azoles block ergosterol synthesis by inhibiting fungal CYP51, which leads to disruption of fungal membrane permeability. In this study, we screened for antifungal activity of an in‐house azole library of 65 compounds to identify hit matter followed by a molecular modeling study for their CYP51 inhibition mechanism. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed derivatives 12 and 13 as highly active. Furthermore, they showed potent antibiofilm activity as well as neglectable cytotoxicity in a mouse fibroblast assay. According to molecular docking studies, 12 and 13 have the necessary binding characteristics for effective inhibition of CYP51. Finally, molecular dynamics simulations of the C. albicans CYP51 (CACYP51) homology model's catalytic site complexed with 13 were stable demonstrating excellent binding.

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New azole derivatives showing antimicrobial effects and their mechanism of antifungal activity by molecular modeling studies

Cited by 55 publications

References 53 publications

The Y137H mutation in the cytochrome P450 FgCYP51B protein confers reduced sensitivity to tebuconazole in Fusarium graminearum

The Y137H mutation in the cytochrome P450 FgCYP51B protein confers reduced sensitivity to tebuconazole in Fusarium graminearum

Synthesis, Molecular Docking Studies, and Antifungal Activity Evaluation of New Benzimidazole-Triazoles as Potential Lanosterol 14α-Demethylase Inhibitors

Antifungal screening and in silico mechanistic studies of an in‐house azole library

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