Jwm. Nissink et al., SUPERPOSITION OF MOLECULES - ELECTRON-DENSITY FITTING BY APPLICATION OF FOURIER-TRANSFORMS, Journal of computational chemistry, 18(5), 1997, pp. 638-645
In this article a new method is described to superimpose molecules usi
ng a crystallographic Fourier transform approach. Superimposed molecul
es, among other purposes, serve as a basis for three-dimensional (3D)
QSAR analyses in drug design and therefore an objective and reproducib
le method of molecule alignment is of major importance. Fourier data a
re generated for hypothetical crystals of cubic symmetry for the compo
unds under consideration. A Patterson-density-based similarity index i
s used to optimize rotational alignment of the molecules. After optimi
zation of rotational orientation, an electron density derived similari
ty index is used to further optimize overlap of electron density as a
function of translation of the molecules. Both similarity indices are
maximized by a simple optimization routine, thus enabling automated su
perposition. The use of Fourier space offers several advantages. First
, rotational and translational parameters can be optimized separately,
thus providing a small parameter space. Second, a limited number of d
ata already provide an adequate, continuous description of the electro
n (or Patterson) density distribution. Third, crystallography provides
simple methods to calculate the Fourier transforms that are needed. T
he resolution of the Patterson (electron) density representation used
for superposition can be varied in a straightforward manner. Results a
re shown for the superposition of two antiviral agents, 2rs1 and 2r04;
the dihydrofolate reductase ligands, methotrexate and dihydrofolate;
and a set of three epsilon-thrombin inhibitors. (C) 1997 by John Wiley
& Sons, Inc.