QSAR studies of antiviral agents using structure-activity maps

Analyses of the structure-activity relationships of purine nucleoside analo gs with anti-HIV activity were performed utilizing structure-activity maps (SAMs). SAMs are chemical structures plotted against their biological activ ities. Molecular descriptors such as number of atoms and bonds of a molecul e (NAB), maximum common substructure (MaCS), and molecular similarity index (MSI) were used to quantify the chemical structures. The MaCS of two molec ules is defined as the substructure with the greatest NAB value common to b oth molecules. The MSI of two molecules X and Y is defined as: MSI(X,Y) = [ MaCS((X,Y))/NAB((X))] x [MaCS((X,Y))/NAB((Y))]. The antiviral activity meas urement used in this study was the 50% effective dose (ED50) in mu M, based on the 50% protection of cells against the cytopathic effect of HIV-1. The SAMs were examined for compounds grouped according to either NAB or MSI(X, Y). The topoisomer groups (based on NAB) and molecular similarity groups (b ased on MSI) were. examined to determine important activity trends utilizin g structural orderings and structural transformations. A structural orderin g is a set of compounds, L, if every set of three compounds in L is colline ar. Three compounds (X, Y, Z) are collinear if compound Y lies between comp ounds X and Z such that TD(X,Z) = TD(X,Y) + TD(Y,Z). The topological distan ce, TD(X,Y), between two molecules, X and Y is defined as TD(X,Y) = NAB((X) ) + NAB((Y)) - 2 MaCS((X,Y)). A structural transformation describes a funct ional group modification to a parent molecule. SAMs were used to systematic ally identify the effects of chemical modification on the anti-HIV activity of purine analogs and to determine the site and type of modifications for improved activity and reduced toxicity of potential antiviral agents.