Rigorous Treatment of Multispecies Multimode Ligand鈭扲eceptor Interactions in 3D-QSAR: CoMFA Analysis of Thyroxine Analogs Binding to Transthyretin
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- 作者：Senthil Natesan ; Tiansheng Wang ; Viera Lukacova ; Vladimir Bartus ; Akash Khandelwal ; Stefan Balaz
- 刊名：Journal of Chemical Information and Modeling
- 出版年：2011
- 出版时间：May 23, 2011
- 年：2011
- 卷：51
- 期：5
- 页码：1132-1150
- 全文大小：1244K
- 年卷期：v.51,no.5(May 23, 2011)
- ISSN：1549-960X
文摘
For a rigorous analysis of the receptor鈭抣igand binding, speciation of the ligands caused by ionization, tautomerism, covalent hydration, and dynamic stereoisomerism needs to be considered. Each species may bind in several orientations or conformations (modes), especially for flexible ligands and receptors. A thermodynamic description of the multispecies (MS), multimode (MM) binding events shows that the overall association constant is equal to the weighted sum of the sums of microscopic association constants of individual modes for each species, with the weights given by the unbound fractions of individual species. This expression is a prerequisite for a precise quantitative characterization of the ligand鈭抮eceptor interactions in both structure-based and ligand-based structure鈭抋ctivity analyses. We have implemented the MS-MM correlation expression into the comparative molecular field analysis (CoMFA), which deduces a map of the binding site from structures and binding affinities of a ligand set, in the absence of experimental structural information on the receptor. The MS-MM CoMFA approach was applied to published data for binding to transthyretin of 28 thyroxine analogs, each forming up to four ionization species under physiological conditions. The published X-ray structures of several analogs, exhibiting multiple binding modes, served as templates for the MS-MM superposition of thyroxine analogs. Additional modes were generated for compounds with flexible alkyl substituents, to identify bound conformations. The results demonstrate that the MS-MM modification improved predictive abilities of the CoMFA models, even for the standard procedure with MS-MM selected species and modes. The predicted prevalences of individual modes and the generated receptor site model are in reasonable agreement with the available X-ray data. The calibrated model can help in the design of inhibitors of transthyretin amyloid fibril formation.