Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using 螖logP As a Tool

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• 作者：Marina Shalaeva ; Giulia Caron ; Yuriy A. Abramov ; Thomas N. O鈥機onnell ; Mark S. Plummer ; Geeta Yalamanchi ; Kathleen A. Farley ; Gilles H. Goetz ; Laurence Philippe ; Michael J. Shapiro
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 27, 2013
• 年：2013
• 卷：56
• 期：12
• 页码：4870-4879
• 全文大小：530K
• 年卷期：v.56,no.12(June 27, 2013)
• ISSN：1520-4804

文摘

This study demonstrates that 螖logP_oct-tol (difference between logP_octanol and logP_toluene) describes compounds propensity to form intramolecular hydrogen bonds (IMHB) and may be considered a privileged molecular descriptor for use in drug discovery and for prediction of IMHB in drug candidates. We identified experimental protocols for acquiring reliable 螖logP_oct-tol values on a set of compounds representing IMHB motifs most prevalent in medicinal chemistry, mainly molecules capable of forming 6-, 7-member IMHB rings. Furthermore, computational 螖logP_oct-tol values obtained with COSMO-RS software provided a good estimate of experimental results and can be used prospectively to assess IMHB. The proposed interpretation method based on 螖logP_oct-tol data allowed categorization of the compounds into 2 groups: with high propensity to form IMHB and poor propensity or poor relevance of IMHB. The relative ¹H NMR chemical shift of an exchangeable proton was used to verify presence of IMHB and to validate the IMHB interpretation scheme.