کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
443269 692696 2016 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Structure-based designing of sordarin derivative as potential fungicide with pan-fungal activity
ترجمه فارسی عنوان
طراحی ساختار مبتنی بر مشتق شده استارین به عنوان قارچ کش بالقوه با فعالیت قارچی
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی تئوریک و عملی
چکیده انگلیسی


• Fungicide Sordarin is not equally effective towards eEF2s across different fungal species.
• Substitutions at positions 521 and 523 (yeast eEF2 numbering) within the ‘Sordarin Specificity Region (SSR)’ are predicted to be crucial for sordarin binding.
• In addition to the SSR mutations, some other mutations within the cavity (termed nonSSR) are likely responsible for complete sordarin resistance of human eEF2.
• Modifications introduced within the sordarin structure that increase favorable contacts with residue at position 521 result effective binding to sordarin-resistant eEF2s.
• One such derivative with 2-aminopyrrole group attached at C61position of sordarin appears to be a potential candidate for broad spectrum antifungal agents.

Fungal infections have become a significant problem for immunosuppressed patients. Sordarin, a promising fungicidal agent, inhibits fungal protein synthesis by impairing elongation factor-2 (eEF2) function. Intriguingly, despite high sequence similarity among eEF2s from different species, sordarin has been shown to inhibit translation specifically in certain fungi while unable to do so in some other fungal species (e.g. Candida parapsilosis and Candida lusitaniae).The sordarin binding site on eEF2 as well as its mechanism of action is known. In a previous study, we have detailed the interactions between sordarin and eEF2 cavities from different fungal species at the molecular level and predicted the probable cause of sordarin sensitivity.Guided by our previous analysis, we aimed for computer-aided designing of sordarin derivatives as potential fungicidal agents that still remain ineffective against human eEF2. We have performed structural knowledge-based designing of several sordarin derivatives and evaluated predicted interactions of those derivatives with the sordarin-binding cavities of different eEF2s, against which sordarin shows no inhibitory action. Our analyses identify an amino-pyrrole derivative as a good template for further designing of promising broad-spectrum antifungal agents. The drug likeness and ADMET prediction on this derivative also supports its suitability as a drug candidate.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Graphics and Modelling - Volume 66, May 2016, Pages 133–142
نویسندگان
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