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The QSAR paradigm is delineated as it evolved and as it is presently used. The methodology used to select appropriate substituents/compounds, parameters, and approaches is addressed. Parameters that are routinely used to define a QSAR are sequestered according to their electronic, hydrophobic, and steric attributes. Indicator variables and molecular structure descriptors are also described. The types of QSAR models that are featured include the linear and parabolic models elucidated by Hansch and the bilinear model developed by Kubinyi. Applications of QSAR are drawn from isolated receptor systems as well as cellular and whole animal studies. The utility of a comprehensive QSAR database that allows for lateral validation from physical organic reactions and other biological systems is described and illustrated.

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In this comprehensive study on the caspase-mediated apoptosis-inducing effect of 51 substituted phenols in a murine leukemia cell line (L1210), we determined the concentrations needed to induce caspase activity by 50% (I50) and utilized these data to develop the following quantitative structure-activity relationship (QSAR) model: log 1/I50 = 1.06 B5(2) + 0.33 B5(3) - 0.18pi(2,4) - 0.92. B5(3) and B5(2) represent steric terms, while pi(2,4) represents the hydrophobic character of the substituents on the ring. The strong dependence of caspase-mediated apoptosis on mostly steric parameters suggests that the process is a receptor-mediated interaction with caspases or mitochondrial proteins being the likely targets. Conversely, cytotoxicity studies of 65 electron-releasing phenols in the L1210 cell line led to the development of the following equation: log 1/ID50 = -1.39sigma+ - 0.28 B5(2,6) + 0.16 log P - 0.58I(2) - 1.04I(1) + 3.90. The low coefficient with log P may pertain to cellular transport that may be enhanced by a modest increase in overall hydrophobicity, while the presence of sigma+ is consistent with the suggestion that radical stabilization is of prime importance in the case of electron-releasing substituents. On the other hand, the QSAR for the interactions of 27 electron-attracting phenols in L1210 cells, log 1/ID50 = 0.56 log P - 0.30 B5(2) + 2.79, suggests that hydrophobicity, as represented by log P is of critical importance. Similar cytotoxicity patterns are observed in other mammalian cell lines such as HL-60, MCF-7, CCRF-CEM, and CEM/VLB. The significant differences between the cytotoxicity and apoptosis QSAR for electron-releasing phenols suggest that cytotoxicity involves minimal apoptosis in most of these substituted monophenols.

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The inhibition constants (Kiapp) were obtained from the action of 68 2,4-diamino-5-(substituted-benzyl)pyrimidines on dihydrofolate reductase from an Escherichia coli strain MB 1428. Subsequently, these results were used to formulate appropriate quantitative structure-activity relationships (QSAR). Once again these equations emphasize the paramount importance of steric/dispersion factors in enhancing antibacterial potency. Hydrophobicity also plays a role, albeit a minor one. Comparisons with the QSAR obtained versus prokaryotic dihydrofolate reductase (DHFR) demonstrate subtle differences in binding behavior between meta and para substituents which may be effectively maximized in the design of more efficacious and selective antibacterial agents. The bacterial and avian QSAR equations can be used to calculate selectivity indices for trimethoprim, tetroxoprim, and two other specially designed 2,4-diamino-5-(substituted-benzyl)pyrimidines.

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