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Journal of Computer-Aided Molecular Design

, Volume 31, Issue 2, pp 163–181 | Cite as

The influence of hydrogen bonding on partition coefficients

  • Nádia Melo Borges
  • Peter W. KennyEmail author
  • Carlos A. Montanari
  • Igor M. Prokopczyk
  • Jean F. R. Ribeiro
  • Josmar R. Rocha
  • Geraldo Rodrigues Sartori
Perspective

Abstract

This Perspective explores how consideration of hydrogen bonding can be used to both predict and better understand partition coefficients. It is shown how polarity of both compounds and substructures can be estimated from measured alkane/water partition coefficients. When polarity is defined in this manner, hydrogen bond donors are typically less polar than hydrogen bond acceptors. Analysis of alkane/water partition coefficients in conjunction with molecular electrostatic potential calculations suggests that aromatic chloro substituents may be less lipophilic than is generally believed and that some of the effect of chloro-substitution stems from making the aromatic π-cloud less available to hydrogen bond donors. Relationships between polarity and calculated hydrogen bond basicity are derived for aromatic nitrogen and carbonyl oxygen. Aligned hydrogen bond acceptors appear to present special challenges for prediction of alkane/water partition coefficients and this may reflect ‘frustration’ of solvation resulting from overlapping hydration spheres. It is also shown how calculated hydrogen bond basicity can be used to model the effect of aromatic aza-substitution on octanol/water partition coefficients.

Keywords

Alkane/water Hydrogen bonding Lipophilicity LogP Octanol/water Molecular design Partition coefficient Polarity Property-based drug design 

Notes

Acknowledgements

We thank FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo; Grant No. 2013/18009-4) and CNPq (Conselho Nacional de Pesquisa; Grant No. 303991/2014-3) for financial support. NMB and IMP thank Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and JFRR and GRS thank CNPq for scholarships. We are grateful to OpenEye Scientific Software for an academic software license. We also thank the two anonymous reviewers of the manuscript for their constructive and insightful comments.

Supplementary material

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Supplementary material 5 (DOCX 19 KB)
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Supplementary material 6 (ZIP 464 KB)

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© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Nádia Melo Borges
    • 1
  • Peter W. Kenny
    • 1
    Email author
  • Carlos A. Montanari
    • 1
  • Igor M. Prokopczyk
    • 1
  • Jean F. R. Ribeiro
    • 1
  • Josmar R. Rocha
    • 1
  • Geraldo Rodrigues Sartori
    • 1
  1. 1.Grupo de Estudos em Química Medicinal – NEQUIMEDInstituto de Química de São Carlos – Universidade de São PauloSão CarlosBrazil

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