Development of Quantitative Structure−Property Relationship Models for Early ADME Evaluation in Drug Discovery. 2. Blood-Brain Barrier Penetration

Ruifeng Liu,†‡ Hongmao Sun,† and Sung-Sau So*†
Discovery Chemistry, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, and Department of Chemistry, East Tennessee State University, Johnson City, Tennessee 37614
J. Chem. Inf. Comput. Sci., 2001, 41 (6), pp 1623–1632
DOI: 10.1021/ci010290i
Publication Date (Web): October 2, 2001
Copyright © 2001 American Chemical Society
†

 Discovery Chemistry, Hoffmann-La Roche Inc.

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‡

 East Tennessee State University.

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*

 Corresponding author phone:  (973)235-2193; fax:  (973)235-2682; e-mail:  sung-sau.so@roche.com. Corresponding address:  Hoffmann-La Roche, Inc.. Preclinical Research and Development, 340 Kingsland Street, Nutley, NJ 07110.

Abstract

A new molecular lipoaffinity descriptor was introduced in this paper to account for the effect of molecular hydrophobicity on blood-brain barrier penetration. The descriptor was defined based on Kier and Hall's atom-type electrotopological state indices. Its evaluation requires 2-D molecular bonding information only. A multiple linear regression equation using this descriptor and molecular weight reproduces the experimental logBB values of 55 training set compounds and 11 test set compounds satisfactorily with statistical parameters nearly identical to the best models based on polar surface area and ClogP. The results indicate that the lipoaffinity descriptor defined in this paper may be a significant descriptor for molecular transport properties across lipid bilayers.

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History

  • Published In Issue November 26, 2001
  • Received March 12, 2001

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