Uncovering abnormal changes in logP after fluorination using molecular dynamics simulations
| Autor: | Kai Liu, Hironori Kokubo |
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| Rok vydání: | 2019 |
| Předmět: |
Indoles
Halogenation Thermodynamics Molecular simulation Molecular Dynamics Simulation Drug molecule 01 natural sciences Force field (chemistry) Molecular dynamics 1-Butanol Alkanes 0103 physical sciences Drug Discovery Computer Simulation Pyrroles Physical and Theoretical Chemistry Sulfonamides 010304 chemical physics Chemistry Water Fluorine 1-Octanol 0104 chemical sciences Computer Science Applications Partition coefficient 010404 medicinal & biomolecular chemistry Dipole Models Chemical Solvents |
| Zdroj: | Journal of Computer-Aided Molecular Design. 33:345-356 |
| ISSN: | 1573-4951 0920-654X |
| Popis: | The fluorination-induced changes in the logP (1-octanol/water partition coefficient) of ligands were examined by molecular dynamics simulations. The protocol and force field parameters were first evaluated by calculating the logP values for n-alkanes, and their monofluorinated and monochlorinated analogs. Then, the logP values of several test sets (1-butanol, 3-propyl-1H-indole, and analogs fluorinated at the terminal methyl group) were calculated. The calculated results agree well with experiment, and the root mean square error values are 0.61 and 0.68 log units for the GAFF and GAFF2 force fields, respectively. Finally, the logP estimation was extended to a drug molecule, TAK-438, for which fluorination-induced abnormal logP reduction has been observed experimentally. This abnormal change was qualitatively reproduced by the molecular dynamics simulations. We found that the abnormal logP reduction can be mainly attributed to the effect of fluorination-induced dipole change. Our results suggest that molecular simulation is a useful strategy to predict the fluorination-induced change in logP for drug discovery applications. |
| Databáze: | OpenAIRE |
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