J. Schnitker et al., OBJECTIVE MODELS FOR STEROID-BINDING SITES OF HUMAN GLOBULINS, Journal of computer-aided molecular design, 11(1), 1997, pp. 93-110
We report the application of a recently developed alignment-free 3D QS
AR method [Crippen, G.M., J. Comput. Chem., 16 (1995) 486] to a benchm
ark-type problem. The test system involves the binding of 31 steroid c
ompounds to two kinds of human carrier protein. The method used not on
ly allows for arbitrary binding modes, but also avoids the problems of
traditional least-squares techniques with regard to the implicit negl
ect of informative outlying data points. It is seen that models of con
siderable predictive power can be obtained even with a very vague bind
ing site description. Underlining a systematic, but usually ignored, p
roblem of the QSAR approach, there is not one unique type of model but
, rather, an entire manifold of distinctly different models that are a
ll compatible with the experimental information. For a given model, th
ere is also a considerable variation in the found binding modes, illus
trating the problems that are inherent in the need for 'correct' molec
ular alignment in conventional 3D QSAR methods.