A molecular shape analysis and quantitative structure-activity relationship investigation of some triazine-antifolate inhibitors of Leishmania dihydrofolate reductase

Molecular shape analysis (MSA) is used to develop quantitative structure-activity relationships (QSARs) for a set of 45 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-substituted-phenyl)-s-triazine inhibitors of Leishmania major dihydrofolate reductase (DHFR). The MSA-QSARs are equally significant to a QSAR developed by R. G. Booth et al. [1987) J. Med. Chem. 30, 1218) using linear free energy descriptors. However, the MSA-QSARs have the same general form as all other QSARs developed for DHFR inhibitors using MSA. Molecular shape, as represented by common overlap steric volume of each inhibitor with a shape reference standard triazine from the set of 45 compounds, and relative lipophilicity account for the large majority of the variance in inhibition potency as a function of substituent choice. A general method of evaluating the impact of different conformational states of flexible substituents upon the form and significance of MSA-QSARs is developed. The results of applying this method to the 45 triazines indicate that the MSA-QSARs are relatively independent of the type of conformation assigned to the large flexible substituents. It is important to note, however, that the types of substituent conformations used in this analysis cannot necessarily be related to an "active" substituent conformation.