TOPOLOGICAL SIMILARITY / DISSIMILARITY INDICATORS: APPLICATION TO CYTOCHROME P450 INHIBITION BY ALCOHOLS
Dan Dragoş, Alina Hegheş, Mihai Medeleanu, Vicenţiu Vlaia, Corina Seiman, Adriana Kaycsa, Dan Ciubotariu · 2004
10 topological indicators of molecular similarity derived from cluster analysis, and based on binary distance measures were examined. 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 pI 50 , that is, the logarithm of reciprocal concentration that causes 50% inhibition) are in the range of 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 the 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. 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 r2 CV =0.736. This supports the hypothesis that the binding of alcohols to the enzymatic site of cytochrome P-450 takes place