کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10585593 | 981368 | 2013 | 23 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Tackling the conformational sampling of larger flexible compounds and macrocycles in pharmacology and drug discovery
ترجمه فارسی عنوان
رفع نمونه های سازش شده از ترکیبات انعطاف پذیر و انعطاف پذیر بزرگتر در مواد دارویی و کشف مواد مخدر
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کلمات کلیدی
Merck Molecular Force FieldMMFFPDBThree-dimensionalOPLSDiel - بخشGraphical user interface - رابط کاربر گرافیکیGUI - رابط کاربری گرافیکیRadius of gyration - شعاع نفوذComputational chemistry - شیمی محاسباتیMacrocycles - ماکروسیکل هاgeneralized Born - متولد متولد شدMolecular Operating Environment - محیط عملیاتی مولکولیConformational sampling - نمونه گیری سازندهMOE - وزارت صنایعMolecular weight - وزن مولکولیProtein Data Bank - پروتئین بانک اطلاعاتیDrug discovery - کشف مواد مخدر
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
چکیده انگلیسی
Computational conformational sampling underpins much of molecular modeling and design in pharmaceutical work. The sampling of smaller drug-like compounds has been an active area of research. However, few studies have tested in details the sampling of larger more flexible compounds, which are also relevant to drug discovery, including therapeutic peptides, macrocycles, and inhibitors of protein-protein interactions. Here, we investigate extensively mainstream conformational sampling methods on three carefully curated compound sets, namely the 'Drug-like', larger 'Flexible', and 'Macrocycle' compounds. These test molecules are chemically diverse with reliable X-ray protein-bound bioactive structures. The compared sampling methods include Stochastic Search and the recent LowModeMD from MOE, all the low-mode based approaches from MacroModel, and MD/LLMOD recently developed for macrocycles. In addition to default settings, key parameters of the sampling protocols were explored. The performance of the computational protocols was assessed via (i) the reproduction of the X-ray bioactive structures, (ii) the size, coverage and diversity of the output conformational ensembles, (iii) the compactness/extendedness of the conformers, and (iv) the ability to locate the global energy minimum. The influence of the stochastic nature of the searches on the results was also examined. Much better results were obtained by adopting search parameters enhanced over the default settings, while maintaining computational tractability. In MOE, the recent LowModeMD emerged as the method of choice. Mixed torsional/low-mode from MacroModel performed as well as LowModeMD, and MD/LLMOD performed well for macrocycles. The low-mode based approaches yielded very encouraging results with the flexible and macrocycle sets. Thus, one can productively tackle the computational conformational search of larger flexible compounds for drug discovery, including macrocycles.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 24, 15 December 2013, Pages 7898-7920
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 24, 15 December 2013, Pages 7898-7920
نویسندگان
I-Jen Chen, Nicolas Foloppe,