Journal of Computer-Aided Molecular Design, 16: 287–295, 2002. KLUWER/ESCOM © 2002 Kluwer Academic Publishers. Printed in the Netherlands. 287 HEPT derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase: QSAR studies agree with the crystal structures Anderson Coser Gaudio a,∗ and Carlos Alberto Montanari b a Departamento de F´ ısica, Centro de Ciências Exatas, Universidade Federal do Esp´ ırito Santo, Campus de Goiabeiras, 29.060-900 Vit´ oria - ES, Brazil; b Departamento de Qu´ ımica, Universidade Federal de Minas Gerais, Campus da Pampulha, 31.270-901 Belo Horizonte - MG, Brazil Received 22 October 2001; Accepted 18 June 2002 Key words: human immunodeficiency virus type 1, reverse transcriptase, quantitative structure-activity relation- ships, molecular modeling, acyclouridine derivatives Summary The interest in the non-nucleoside inhibitors (NNIs) to the reverse transcriptase (RT) as anti-AIDS agents has grown in the last ten years. The compound 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) is the precursor of the most studied class of NNIs, from which hundreds of derivatives have been synthesized and tested. There are at least twelve QSAR studies about the HEPT derivatives as RT inhibitors. Most of the predictions derived by these studies are related to the nature of the active site near the substituents at positions N-1 and C-5, and at the C-6 phenyl ring. The validity of these models has been checked against the 3-D structure of HIV 1 RT-HEPT complexes available. Most of these predictions were confirmed at the molecular level. Abbreviations: AIDS, acquired immunodeficiency syndrome; CoMFA, comparative molecular field analysis; DNA, deoxyribonucleic acid; HEPT, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine; HIV, human immunodefi- ciency virus; PDB, protein databank; PLS, partial least squares; QSAR, quantitative structure-activity relationships; RCSB, Research Collaboratory for Structural Bioinformatics; RT, reverse transcriptase. Introduction The acquired immunodeficiency syndrome (AIDS) is probably the most investigated disease since it was discovered in the earlier eighties. Huge amounts of money and human effort have been spent in the search of a possible cure, but in spite of these, the AIDS virus is still resisting and no absolute successful chemother- apy is available to date. The AIDS virus is a retrovirus that belongs to the lentivirus subfamily. Two of its enzymes became the preferred targets for developing anti-AIDS drugs: reverse transcriptase (RT) [1–3] and protease [4–8]. The RT is responsible for making a copy of the viral RNA into a complementary DNA as soon as the virus enters the host cell, a process named ∗ Corresponding author: Phone: 0055-27-3335.2483; Fax: 0055-27- 3335.2823; e-mail: anderson@npd.ufes.br transcription. Protease is mainly involved in the virion maturation, a later stage in the virus life cycle. Although many drugs are currently available in the market, the search for new HIV enzyme in- hibitors is still going on, especially because of the induced resistance most of these drugs cause. Tanaka and co-workers studied a series of RT in- hibitors derived from 1-[(2-hydroxyethoxy)methyl]- 6-(phenylthio)thymine (HEPT; Structure 1) [9–11]. They also performed structure-activity studies about the influence of the chemical groups of structure 1 on the HIV-1 RT inhibitory activity [12–16]. The quantitative biological data presented by Tanaka and co-workers in these papers is the basis of all the quan- titative structure-activity relationship (QSAR) studies published to date. The HEPT derivatives are probably the most stud- ied group of non-nucleoside inhibitors to HIV-1 RT.