Biophysical Limits of Protein鈥揕igand Binding

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• 作者：Richard D. Smith ; Alaina L. Engdahl ; James B. Dunbar ; Jr. ; Heather A. Carlson
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2012
• 出版时间：August 27, 2012
• 年：2012
• 卷：52
• 期：8
• 页码：2098-2106
• 全文大小：494K
• 年卷期：v.52,no.8(August 27, 2012)
• ISSN：1549-960X

文摘

In classic work, Kuntz et al. (Proc. Nat. Acad. Sci. USA1999, 96, 9997鈥?0002) introduced the concept of ligand efficiency. Though that study focused primarily on drug-like molecules, it also showed that metal binding led to the greatest ligand efficiencies. Here, the physical limits of binding are examined across the wide variety of small molecules in the Binding MOAD database. The complexes with the greatest ligand efficiencies share the trait of being small, charged ligands bound in highly charged, well buried binding sites. The limit of ligand efficiency is 鈭?.75 kcal/mol路atom for the protein鈥搇igand complexes within Binding MOAD, and 95% of the set have efficiencies below a 鈥渟oft limit鈥?of 鈭?.83 kcal/mol路atom. On the basis of buried molecular surface area, the hard limit of ligand efficiency is 鈭?17 cal/mol路脜², which is in surprising agreement with the limit of macromolecule鈥損rotein binding. Close examination of the most efficient systems reveals their incredibly high efficiency is dictated by tight contacts between the charged groups of the ligand and the pocket. In fact, a misfit of 0.24 脜 in the average contacts inherently decreases the maximum possible efficiency by at least 0.1 kcal/mol路atom.