Beyond the 2-D Chemical Structure
N. C. COHEN · ACS symposium series · 1979
Abstract QSAR theories are convenient for the design of new analogs of a Known active compound but these theories are not always able to go beyond the chemical frame of the particular family studied. Considering structure-activity studies in the light of the three dimensional specificity of molecular interactions between drugs and receptors, conformational properties appear to be essential. To allow the design of new molecular architectures which could be able to mimic the essential features of known active compounds, it is necessary to evaluate to what extent different molecules can mimic the spatial arrangement of atoms of a known active compound. The criterion of minimization of the total exposed molecular area of sets of overlapping molecules appears to be a powerful tool for revealing the 3-D mimetism between several molecules. During the minimization the molecules are not rigid but free to move and modify their geometries, provided that the molecular energies do not increase by more than a pre-established amount. Such calculations can reveal the biologically relevant molecular geometries and the possible associated pharmacophores. It is possible for the 3-D mimetism to be, not only geometrical but also electronic. Both properties can be visualized in a "four dimensional symbolism" which consists of a view of the envelope of the molecules studies, on the surface of which, energy contours of the electrostatic molecular potential are drawn. An example will be presented to illustrate the possibilities of this approach.