Multimode ligand binding in receptor site modeling: implementation in CoMFA.

Receptor site modeling methods usually use one binding mode (conformation and/or orientation) for each ligand in a 1:1 complex with receptor. Multiple modes should be considered instead because (1). they have frequently been observed experimentally; (2). in a series, ligands can bind in single yet different modes; and (3). a series may only exhibit one but unknown mode and a few plausible modes must be examined. For multimode binding, the observed ligand/receptor association constant is the sum of the association constants that characterize individual binding modes. This relation, when applied to Comparative Molecular Field Analysis (CoMFA), results in a dependence of the observed binding energy on the probe energies that is nonlinear in optimized parameters. The dependence was linearized to allow parameter optimization by the partial least-squares method that was used iteratively until self-consistency. In addition to the standard CoMFA output, the procedure objectively selects one or a few optimal binding modes out of a dozen or more modes that are considered for each ligand. The approach was applied to published data for binding of 34 polychlorinated dibenzofurans to the aryl hydrocarbon receptor. Descriptive and predictive abilities of the 16-mode model were significantly better than for the one-, two-, and four-mode models. Predominantly, edge-aligned modes were selected that are seldom used in CoMFA. Since inclusion of multimode binding only changes the form of the correlation equation and does not affect the number of optimized parameters, the improvement is believed to be due to a more realistic description.