COMPUTER-ASSISTED MOLECULAR DESIGN AND BIOPHORE DETERMINATION - APPLICATION TO AIDS DRUGS

The search of drugs against the acquired immunodeficiency syndrome (AIDS) has been one of the main research subjects during the last decade. In this work an exhaustive search of active biophores against AIDS using the system APEX-3D (BIOSYM) is presented. A total of 83 HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine) derivative molecules of known activity were considered. Molecular geometries were optimized with molecular mechanics and molecular dynamic methods (DISCOVER) and were classified in 4 activity classes. Within this data base and with the help of quantum mechanic methods (MOPAC 6.0), 3252 biophores having good statistical parameters were found. The best biophore of class I (very active) has 4 reactive centers with a cyclic reactive center (CRC) which is characteristic for biophores of class I. This CRC does not occur as a reactive center in the rest of the activity classes. That is in agreement with experimental data showing an interaction between a cyclic reactive center and a hydrophobic pocket of the reverse transcriptase enzyme. Analysis of the biophores obtained in this work allowed for the proposition of 3'-F-5'-phenyl-3',5'-dideoxythymidine and 3'benzyl-3'-deoxythymidine as potentially active drugs taking in consideration statistical indexes which make their synthesis and further biological essay a promising task.