کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9139992 | 1163390 | 2005 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase
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کلمات کلیدی
Naphthoic acids2,6-Naphthalenedicarboxylic acid - اسید 2،6-نفتالینیکاربوکیلیکcrystallography - بلورنگاری، بلورشناسی یا کریستالوگرافیlactate dehydrogenase - لاکتات دهیدروژناز LDH - لاکتات دهیدروژناز به صورت مختصر شده LDH Malaria - مالاریاMethyl - متیلPlasmodium falciparum lactate dehydrogenase - پلاسمودیوم فالسیپاروم لاکتات دهیدروژنازGossypol - گسسیپول
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شناسی مولکولی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Gossypol is a di-sesquiterpene natural-product in the form of a functionalised binaphthyl and is isolated from cotton plants. The compound has long been known to exhibit anti-malarial and other biological activities. Previous studies have indicated that compounds of this type target Plasmodium falciparum lactate dehydrogenase (pfLDH), an essential enzyme for energy generation within the parasite. In this study, we report that simple naphthalene-based compounds, the core of the gossypol structure, exhibit weak inhibition of the parasite lactate dehydrogenase. Crystal structures of the complexes formed by binding of these naphthalene-based compounds to their target enzyme have been used to delineate the molecular features likely to form the gossypol binding site. Two modes of binding are observed: one overlapping the pyruvate but not the co-factor site, the other bridging the binding sites for the co-factor nicontinamide group and pyruvate substrate. This latter site encompasses molecular features unique to Plasmodium forms of LDH and is likely to represent the mode of binding for gossypol derivatives that show selectivity for the parasite enzymes. We also report a substrate analogue that unexpectedly binds within the adenine pocket of the co-factor groove. Although these core pharmacophore-like molecules only exhibit low levels of inhibitory activity, these molecular snapshots provide a rational basis for renewed structure-based development of naphthalene-based compounds as anti-malarial agents.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular and Biochemical Parasitology - Volume 142, Issue 2, August 2005, Pages 137-148
Journal: Molecular and Biochemical Parasitology - Volume 142, Issue 2, August 2005, Pages 137-148
نویسندگان
Rebecca Conners, Felix Schambach, Jon Read, Angus Cameron, Richard B. Sessions, Livia Vivas, Anna Easton, Simon L. Croft, R. Leo Brady,