Chapter 19
Comparative QSAR: Understanding Hydrophobic Interactions
Downloaded by UNIV OF OKLAHOMA on October 26, 2014 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0606.ch019
Corwin Hansch Department of Chemistry, Pomona College, 645 North College Avenue, Claremont, CA 91711-6338
In our current database of 3000 bio QSAR less than 10% lack hydrophobic terms. It is of particular interest that some of these are for QSAR in whole organisms. Various examples are given. A surprising number involve electrophiles. Also in instances where reaction has been shown to occur with a receptor without apparent hydrophobic interactions, the same effect is present in the QSAR for the cell or organism. Since the systematic development of octanol/water partitioning as a model for hydrophobic interactions began over 30 years ago (7), logP and π have been important in the derivation of thousands of quantitative structure-activity relationships (QSAR). Clearly the methodology has proved to be valuable in the design of bioactive and less toxic chemicals (2). Nevertheless, the field has grown in a haphazard manner with most workers doing little to show how their new QSAR fits in with what has been done. In searching for more order we have developed an easily searchable computerized database of about 6,000 QSAR about evenly divided between the purely chemical and biological fields {3,4). It is hoped that this report will illustrate how such a database can be used by focusing on QSAR which do not contain a hydrophobic term or which contain a small negative term. A search of our present database, except those for macromolecules and isolated enzymes where membrane penetration or interaction with hydrophobic cell components is not possible, finds 1918 QSAR. Eliminating those with hydrophobic terms yields 143 equations (7.5%). In a number of these it is likely that hydrophobic terms have been missed because of poor experimental design resulting in collinearity between steric and hydrophobic properties. Thus, we see that it is rather unusual to find examples where hydrophobic interactions can be neglected. Finding such a QSAR means that extra effort should be made to understand the meaning behind it. Organic compounds can undergo two types of hydrophobic interactions: 1) specific interaction with a hydrophobic part of a receptor. 2) More or less nonspecific interactions with macromolecules (eg. serum proteins) and membranes. Little has been done to delineate these two processes. It is generally assumed that small molecules (MW < 500) penetrate membranes by hydrophobically facilitated passive diffusion; however, size can be very critical (5).
0097-6156/95/0606-0254$12.00/0 © 1995 American Chemical Society In Classical and Three-Dimensional QSAR in Agrochemistry; Hansch, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
19. HANSCH
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Comparative QSAR
Q S A R Where D N A is the Target
Downloaded by UNIV OF OKLAHOMA on October 26, 2014 | http://pubs.acs.org Publication Date: May 5, 1995 | doi: 10.1021/bk-1995-0606.ch019
We first consider QSAR which likely correlate reactions with D N A . In a summary of QSAR for bacterial mutagenesis (6), 11 examples were found for aromatic amines and nitro compounds, nitrosoamines, nitrofurans and 2-arninobenzimidazoles acting on a variety of bacterial cells. A l l of these compounds require activation by microsomal S9 or cytosolic reductase, and hydrophobic terms are essential. In ten of the 11 examples, the coefficient with the hydrophobic term is essentially 1. However, for the following four examples of direct acting electrophilic mutagens, hydrophobic terms were of no help, only electronic terms were essential (6).
1
2
3
4
One must bear in mind that these studies were made on relatively small sets of compounds with relatively small substituents. Compounds with larger hydrophobic groups, say long alkyl units, might require hydrophobic terms. The mutagenicity of the following two direct acting alkylating agents is related to this point. R1OSO2R2 6
RlOS0 Me 5 2
In the two QSAR for the above sulfonate esters it was essential to parameterize R i using π, but despite wide variation in the hydrophobicity of R no parameterization was needed for this part of the molecule (
