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.