A structure-activity relationship study of HEPT-analog compounds with anti-HIV activity

The molecular orbital method PM3 is employed to calculate a set of molecular descriptors (variables) for 36 deoxy analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) with anti-HIV-l activity. Pattern recognition methods, principal component analysis (PCA) and stepwise discriminant analysis (SDA) were employed in order to reduce dimensionality and investigate which subset of variables should be more effective for classifying the HEPT-analog compounds according to their degree of anti-HIV-l activity. The PCA showed that the variables log P (partition coefficient), MR (molecular refractivity), Delta H-f (heat of formation), Q(N) (net atomic charge on atoms 2 and 3), and chi (Mulliken's electronegativity) are responsible for the separation between compounds with higher and lower anti-HIV-1 activity. By using the SDA we have found the following descriptors as responsible for the separation between the active and less active compounds: log P (partition coefficient), chi (Mulliken's electronegativity), mu (dipole moment), Q(4) (net atomic charge on atom 4), and t(2) (torsional angle). From the SDA we present a prediction rule for classifying new HEPT-analog compounds with anti-HIV-l activity. (C) 2000 Elsevier Science B.V. All rights reserved.