MINIMAL TOPOLOGICAL DIFFERENCE (MTD). QSAR STUDY ON A SERIES OF HEPT DERIVATIVES WITH ANTI-HIV ACTIVITY
Corina Seiman1, Marius Olah1,
Lidia Izvernariu2, Dan Drago2 Remus
Nutiu1, Ciprian Ciubotariu3, and Dan
Ciubotariu2
1 West University of Timisoara, Faculty of Chemistry-Biology-Geography, Department of Organic Chemistry, Str. Pestalozzi No.16, 1900 Timisoara, ROUMANIE
2 University of
Medicine and Pharmacy, Faculty of Pharmacy, Department of Organic Chemistry,
P-a Eftimie Murgu no.2, 1900 Timisoara, ROUMANIE
3 Technical
University “Politehnica”, Faculty of Automation and Computer Sciences,
Department of Computer Sciences, 1900 Timisoara, ROUMANIE
In this work we
present the essentials of MTD method together with its application for QSAR
study of a series of 6-(phenylthio)-thymines substituted in 1- and 5-positions
and in phenyl ring. These so-called HEPT derivatives are non-nucleoside
inhibitors of reverse transcriptase (RT) enzyme, which control the reverse
transcription of genomic RNA into double-stranded DNA. This process is central
to the replication of HIV.
MM+ and AM1
computer programs have optimized the geometries of HEPT derivatives; a
conformational analysis was also performed. On the basis of these computational
results, the hypermolecule H was constructed, seeking the maximal superposition
of 25 HEPT derivatives. H describes HEPT–RT complex and allows the mapping of
receptor space by using the MTD algorithm.
A good
correlation (r=0.836) between log (1/C) values of these HEPT derivatives and
the corresponding MTD parameters was obtained. The introduction of
hydrophobicity, as calculated log (P) values, improves the correlation
(r=0.947).
The obtained
results reveal the importance of steric and hydrophobic interactions in the
HEPT–RT complex. The MTD optimized receptor map offers some insights about the
beneficial and detrimental zones of HEPT derivatives.