Binding Affinity Prediction for Ligands and Receptors Forming Tautomers and Ionization Species: Inhibition of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2)

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• 作者：Senthil Natesan ; Rajesh Subramaniam ; Charles Bergeron ; Stefan Balaz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2035-2047
• 全文大小：515K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

Treatment of ionization and tautomerism of ligands and receptors is one of the unresolved issues in structure-based prediction of binding affinities. Our solution utilizes the thermodynamic master equation, expressing the experimentally observed association constant as the sum of products, each valid for a specific ligand鈥搑eceptor species pair, consisting of the association microconstant and the fractions of the involved ligand and receptor species. The microconstants are characterized by structure-based simulations, which are run for individual species pairs. Here we incorporated the multispecies approach into the QM/MM linear response method and used it for structural correlation of published inhibition data on mitogen-activated protein kinase (MAPK)-activated protein kinase (MK2) by 66 benzothiophene and pyrrolopyridine analogues, forming up to five tautomers and seven ionization species under experimental conditions. Extensive cross-validation showed that the resulting models were stable and predictive. Inclusion of all tautomers and ionization ligand species was essential: the explained variance increased to 90% from 66% for the single-species model.