Assessing the Accuracy and Performance of Implicit Solvent Models for Drug Molecules: Conformational Ensemble Approaches

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• 作者：Michal Kol谩艡 ; Jind艡ich Fanfrl铆k ; Martin Lep拧铆k ; Flavio Forti ; F. Javier Luque ; Pavel Hobza
• 刊名：The Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：May 16, 2013
• 年：2013
• 卷：117
• 期：19
• 页码：5950-5962
• 全文大小：583K
• 年卷期：v.117,no.19(May 16, 2013)
• ISSN：1520-5207

文摘

The accuracy and performance of implicit solvent methods for solvation free energy calculations were assessed on a set of 20 neutral drug molecules. Molecular dynamics (MD) provided ensembles of conformations in water and water-saturated octanol. The solvation free energies were calculated by popular implicit solvent models based on quantum mechanical (QM) electronic densities (COSMO-RS, MST, SMD) as well as on molecular mechanical (MM) point-charge models (GB, PB). The performance of the implicit models was tested by a comparison with experimental water鈥搊ctanol transfer free energies (螖G_ow) by using single- and multiconformation approaches. MD simulations revealed difficulties in a priori estimation of the flexibility features of the solutes from simple structural descriptors, such as the number of rotatable bonds. An increasing accuracy of the calculated 螖G_ow was observed in the following order: GB1 PB < GB7 MST < SMD COSMO-RS with a clear distinction identified between MM- and QM-based models, although for the set excluding three largest molecules, the differences among COSMO-RS, MST, and SMD were negligible. It was shown that the single-conformation approach applied to crystal geometries provides a rather accurate estimate of 螖G_ow for rigid molecules yet fails completely for the flexible ones. The multiconformation approaches improved the performance, but only when the deformation contribution was ignored. It was revealed that for large-scale calculations on small molecules a recent GB model, GB7, provided a reasonable accuracy/speed ratio. In conclusion, the study contributes to the understanding of solvation free energy calculations for physical and medicinal chemistry applications.