کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
444346 692967 2012 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Toward understanding the molecular basis for chemical allosteric modulator design
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی تئوریک و عملی
پیش نمایش صفحه اول مقاله
Toward understanding the molecular basis for chemical allosteric modulator design
چکیده انگلیسی

Among the regulation mechanisms of cellular function, allosteric regulation is the most direct, rapid and efficient. Due to the wider receptor selectivity and lower target-based toxicity, compared with orthosteric ligands, allosteric modulators are expected to play a larger role in pharmaceutical research and development. However, current difficulties, such as a low affinity and unknown structural features of potential allosteric small-molecules, usually obstruct the discovery of allosteric modulators. In this study, we compared known allosteric modulators with various compounds from different databases to unveil the structural and qualitative characteristics of allosteric modulators. The results show that allosteric modulators generally contain more hydrophobic scaffolds and have a higher structural rigidity, i.e., less rotatable bonds and more rings. Based on this analysis, an empirical rule was defined to determine the structural requirements for an allosteric modulator. It was found that a large proportion of allosteric modulators (80%) can be successfully retrieved by this “allosteric-like” filter, which shows good discriminatory power in identifying allosteric modulators. Therefore, the study provides deeper insight into the chemical properties of allosteric modulators and has a good potential for the design or optimization of allosteric compounds.

.Figure optionsDownload high-quality image (169 K)Download as PowerPoint slideHighlights
► We analyzed the structural and qualitative characteristics of chemical allosteric modulators.
► Allosteric modulators are generally constructed by higher structural rigidity and hydrophobic scaffold.
► An “allosteric-like” rule is defined for the identification of allosteric modulators.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Graphics and Modelling - Volume 38, September 2012, Pages 324–333
نویسندگان
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