Abstract: MATH/CHEM/COMP 2002, Dubrovnik, June 24-29, 2002

QSAR Studies of a Series of 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)-thymine Derivatives by Means of Minimal Topological Difference (MTD) Method

Corina Seiman¹, Marius Olah¹, Ciprian Ciubotariu², and Dan Ciubotariu³

¹West University of Timisoara, Faculty of Chemistry-Biology-Geography, Department of Organic Chemistry, St. Pestalozzi No.16, 1900 Timisoara, Romania

²“Politehnica” Technical University, Faculty of Automation and Computer Sciences, Department of Computer Sciences, 1900 Timisoara, Romania

³University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Organic Chemistry, P-ţa Eftimie Murgu No.2, 1900 Timisoara, Romania

Quantitative structure-activity relationships have been formulated for the anti-HIV activity of a series of 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)-thymine (HEPT) derivatives. These compounds are no-nucleoside inhibitors of reverse transcriptase (RT) enzyme.

The geometries of HEPT molecules have been optimized by means of MM+ and AM1 computer programs. They have been used as input for the MTD method, in order to map the receptor space of RT enzyme. The MTD values are measures for steric misfit that depends not only on molecular shape of HEPT compounds, but also on the receptor. The MTD allows a guess of the shape of the receptor cavity.

We have developed four QSAR models using the MTD values, together with other hydrophobic and steric indicators. The obtained results are good: the correlation coefficients (r) are in the range 0.900 – 0.960. The QSAR equations suggest several hydrophobic and steric requirements of HEPT derivatives for a significant anti-HIV activity. The optimized receptor map, as resulted by MTD method application, offers some insights about the beneficial and the detrimental zones of the HEPT-RT complex.