Abstract: MATH/CHEM/COMP 2002, Dubrovnik, June 24-29, 2002
QSAR ANALYSIS OF SOME TOPOLOGICAL SIMILARITY/DISSIMILARITY INDICATORS.
APPLICATION FOR THE STUDY OF INHIBITION OF MICROSOMAL p-HYDROXYLATION OF ANILINE BY ALCOHOLS
Dan Ciubotariu1, Marian Pasere1, Mihai Medeleanu2, Marius Olah3,
Corina Seiman3, Dan Dragos1, and Ciprian Ciubotariu4
1University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Organic Chemistry, P-ta Eftimie Murgu No.2, 1900 Timisoara, Romania
2Faculty of Chemical Engineering, “Politehnica” Technical University, St. Bocsa 6, 1900 Timisoara, Romania
3West University of Timisoara, Faculty of Chemistry-Biology-Geography, 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 p-hydroxylation of aniline (A is pI50, 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 cross-validation coefficient was r2CV = 0.736. This supports the hypothesis that the binding of alcohols to the enzymatic site of cytochrome P-450 takes place by a two-stage mechanism, so-called the “zipper” mechanism.