Abstract: MATH/CHEM/COMP 2002, Dubrovnik,
June 2429, 2002

QSAR ANALYSIS OF SOME TOPOLOGICAL
SIMILARITY/DISSIMILARITY INDICATORS. APPLICATION FOR THE STUDY OF INHIBITION OF MICROSOMAL
pHYDROXYLATION OF ANILINE BY ALCOHOLS
Dan Ciubotariu^{1}, Marian Pasere^{1}, Mihai Medeleanu^{2},
Marius Olah^{3}, Corina Seiman^{3}, Dan Dragos^{1}, and Ciprian Ciubotariu^{4} ^{1}University of
Medicine and Pharmacy, Faculty of Pharmacy, Department of Organic Chemistry,
Pta Eftimie Murgu No.2, 1900 Timisoara, Romania ^{2}Faculty of Chemical Engineering,
“Politehnica” Technical University, St. Bocsa 6, 1900 Timisoara, Romania ^{3}West University of Timisoara, Faculty of
ChemistryBiologyGeography, Department of Organic Chemistry, St. Pestalozzi
No.16, 1900 Timisoara, Romania ^{ } ^{4}“Politehnica” Technical University, Faculty of Automation and
Computer Sciences, Department of Computer Sciences, St. Vasile Parvan No. 1,
1900 Timisoara, Romania Commonly, molecules can be described
in three distinct ways: (i)
by their molecular graphs, (ii)
by their atom type and atom positions, or (iii)
by their molecular fields. The notion of similarity is
strongly dependent on the current use to which similarity is put. Therefore
different measures of similarity have to be formulated for each eventual use.
In this paper we examine 10
topological indicators of molecular similarity derived from cluster analysis,
and based on binary distance measures. The correlation coefficients (r) between
these similarity measures and the biological activity (A) of a series of 22
alkyl alcohols that competitively inhibit the microsomal phydroxylation of
aniline (A is pI_{50}, that is, the logarithm of reciprocal
concentration that causes 50% inhibition) are in the range 0.032 – 0.907. We
also propose a topological similarity/dissimilarity measure (TSDM) developed
on the basis of original Minimal Topological Difference (MTD) method, named
MSD. Thus, the bioactive molecules are treated as hydrogen depleted graphs
and the geometrical congruencies of the molecule with highest activity vs.
compared molecules are performed seeking the maximal superposition. The TSDM
was obtained by normalization of MSD values. The range of variation is [0,1].
A value of TSDM close to 1 implies a high topological similarity. The degree
of dissimilarity is maximum if TSDM = 0, and a value of TSDM = 0.5 represents
a natural quantitative threshold. Therefore, the TSDM models these two
concepts – topological similarity and dissimilarity – on the same scale
[1,0]. The results obtained by QSAR analysis of the same series of alcohols
with TSDM values were: the correlation coefficient r = 0.944 and the
crossvalidation coefficient was r^{2}_{CV }= 0.736. This
supports the hypothesis that the binding of alcohols to the enzymatic site of
cytochrome P450 takes place by a twostage mechanism, socalled the “zipper”
mechanism. 