Construction of antifungal dual-target (SE, CYP51) pharmacophore models and the discovery of novel antifungal inhibitors

Dong, Yue; Liu, Min; Wang, Jian; Ding, Zhuang; Sun, Bin

doi:10.1039/c9ra03713f

Cited by 26 publications

(14 citation statements)

References 31 publications

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“…According to the 2D diagram generated by the Maestro program ( Figure 7 ), it is notable that, in addition to the possibility of an interaction of the hydrogen bond type with residue Ile–423, monomethylsulochrin would also be able to establish a long chain of hydrophobic interactions with the active site of the protein. Studies reported in the literature, with the structure of CYP51, revealed that the hydrophobic interactions that its catalytic crack is capable of performing can be considered the main driving force for the binding of ligands ( Dong et al., 2019 ; Shi et al., 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…Analyzing the 3D interaction diagram ( Figure 8 ), it is possible to observe that the structure of monomethylsulochrin is easily allocated to the active site of CYP51, favoring the enzyme-substrate interaction to be less sensitive to the solvent of the biological medium ( Dong et al., 2019 ). This fact suggests that the parameters of the docking calculation performed here were correctly selected, aiming at good results and a lower computational cost.…”

Section: Resultsmentioning

confidence: 99%

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Monomethylsulochrin isolated from biomass extract of Aspergillus sp. against Leishmania amazonensis: In vitro biological evaluation and molecular docking

Silva-Silva

Moreira

Watanabe

et al. 2022

Front. Cell. Infect. Microbiol.

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Leishmaniasis represents a serious world health problem, with 1 billion people being exposed to infection and a broad spectrum of clinical manifestations with a potentially fatal outcome. Based on the limitations observed in the treatment of leishmaniasis, such as high cost, significant adverse effects, and the potential for drug resistance, the aim of the present study was to evaluate the leishmanicidal activity of the compounds pseurotin A and monomethylsulochrin isolated from the biomass extract of Aspergillus sp. The chromatographic profiles of the extract were determined by high-performance liquid chromatography coupled with a diode-array UV-Vis detector (HPLC-DAD-UV), and the molecular identification of the pseurotin A and monomethylsulochrin were carried out by electrospray ionization mass spectrometry in tandem (LC-ESI-MS-MS) and nuclear magnetic resonance (NMR). Antileishmanial activity was assayed against promastigote and intracellular amastigote of Leishmania amazonensis. As a control, cytotoxicity assays were performed in non-infected BALB/c peritoneal macrophages. Ultrastructural alterations in parasites were evaluated by transmission electron microscopy. Changes in mitochondrial membrane potential were determined by flow cytometry. Only monomethylsulochrin inhibited the promastigote growth (IC50 18.04 ± 1.11 µM), with cytotoxicity to peritoneal macrophages (CC50 5.09 91.63 ± 1.28 µM). Activity against intracellular amastigote forms (IC50 5.09 ± 1.06 µM) revealed an increase in antileishmanial activity when compared with promastigotes. In addition to a statistically significant reduction in the evaluated infection parameters, monomethylsulochrin altered the ultrastructure of the promastigote forms with atypical vacuoles, electron-dense corpuscles in the cytoplasm, changes at the mitochondria outer membrane and abnormal disposition around the kinetoplast. It was showed that monomethylsulochrin leads to a decrease in the mitochondrial membrane potential (25.9%, p = 0.0286). Molecular modeling studies revealed that monomethylsulochrin can act as inhibitor of sterol 14-alpha-demethylase (CYP51), a therapeutic target for human trypanosomiasis and leishmaniasis. Assessed for its drug likeness, monomethylsulochrin follows the Lipinski Rule of five and Ghose, Veber, Egan, and Muegge criteria. Furthermore, monomethylsulochrin can be used as a reference in the development of novel and therapeutically useful antileishmanial agents.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Monomethylsulochrin isolated from biomass extract of Aspergillus sp. against Leishmania amazonensis: In vitro biological evaluation and molecular docking

Silva-Silva

Moreira

Watanabe

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Molecular docking has shown great advancement in the predictions of therapeutic interventions by predicting bound conformations and free energies of binding for small-molecule ligands to macromolecular targets (protein) (El-Hachem et al, 2017). It is used in the evaluation of the binding mode of inhibitors and receptors to guide the optimization of lead compounds (Dong et al, 2019). The rule of thumb is "the higher the binding affinity, the lower the inhibition constant", and vice-versa (Ferreira et al, 2015).…”

Section: Molecular Docking Analysismentioning

confidence: 99%

Antifungal Activities of Phytochemicals from Annona muricate (Sour Sop): Molecular Docking and Chemoinformatics Approach

Abdul-Hammed

Adedotun²,

Adegoke³

et al. 2022

Trad.Med.J

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Fungal infection has become a persistent problem in humans and is sometimes life-threatening in immune-compromised individuals. This work aims to study phytochemicals from Annona muricata (sour sop) as probable antifungal agents against Candida albicans sterol 14α-demethylase target receptor by Computer Aided-Drug Design (CADD) approach using voriconazole and fluconazole as standard drugs. A modern method of drug discovery by molecular docking and chemoinformatics was used to screen 131 isolated phytochemicals with medicinal properties from Annona muricata against Candida albicans ‘sterol 14α-demethylase, a prominent target receptor for most anti-fungal drugs, towards the development of new anti-fungal therapeutic agents and a new approach to treat patients with fungal infections. The compounds were all subjected to analyses like ADMET, drug-likeness, bioactivity, oral-bioavailability and PASS. The results of the docking simulation and chemoinformatics analyses showed that muricin M (-7.9 kcal/mol), chlorogenic acid (-8.2 kcal/mol), roseoside (-8.5 kcal/mol) and caffeoylquinic acid (-8.1 kcal/mol) are potential drug candidates for treating fungal infections due to their excellent properties such as binding affinities, ADMET profile, drug-likeness, bioactivity, binding mode and interactions with the target receptor. Thus, muricin M, chlorogenic acid, roseoside and caffeoylquinic acid are recommended for further analyses towards the development of further antifungal drugs.

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“…15 1, 3, 4-Oxadiazole block the 14α-demethylation of lanosterol into ergosterol, which is a major component of fungal cytoplasmic membranes and a bioregulator of membrane asymmetry, fluidity and integrity. [16][17][18][19][20][21][22][23][24][25] https://doi.org/10.18231/j.ctppc.2022.015 2582-5062/© 2022 Innovative Publication, All rights reserved.…”

Section: Introductionmentioning

confidence: 99%

Design, molecular docking studies and ADME prediction of 2, 5-disubstituted 1, 3, 4-oxadiazole derivatives as CYP51 inhibitor for antimicrobial activity

Jadhav¹,

Gadekar²,

Jadhav³

et al. 2022

CTPPC

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The 1, 3, 4-Oxadiazole nucleus offers a wide range of applications in hetero cyclic chemistry, including antimicrobial medicine. A series of the 2, 5-disubstituted 1, 3, 4-Oxadiazole derivatives were designed and study was performed against the ergosterol biosynthesis as an antimicrobial target. The drug-likeness properties of the designed compounds were predicted. All the designed compounds showed good ADME properties and investigated for CYP51 inhibitory activity. According to molecular docking studies, all compounds showed better interaction with target protein and could be the potent inhibitor of ergosterol biosynthesis. The designed 2, 5-disubstituted 1, 3, 4-Oxadiazole derivatives analogs could be safer and more or equivalent effective antimicrobial agents.

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Construction of antifungal dual-target (SE, CYP51) pharmacophore models and the discovery of novel antifungal inhibitors

Abstract: Fungal infections and drug-resistance are rapidly increasing with the deterioration of the external environment.

Cited by 26 publications

References 31 publications

Monomethylsulochrin isolated from biomass extract of Aspergillus sp. against Leishmania amazonensis: In vitro biological evaluation and molecular docking

Monomethylsulochrin isolated from biomass extract of Aspergillus sp. against Leishmania amazonensis: In vitro biological evaluation and molecular docking

Antifungal Activities of Phytochemicals from Annona muricate (Sour Sop): Molecular Docking and Chemoinformatics Approach

Design, molecular docking studies and ADME prediction of 2, 5-disubstituted 1, 3, 4-oxadiazole derivatives as CYP51 inhibitor for antimicrobial activity

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