INTERVALS AND THE DEDUCTION OF DRUG-BINDING SITE MODELS

In the search for new drugs, it often occurs that the binding affiniti es of several compounds to a common receptor macromolecule are known e xperimentally, but the structure of the receptor is not known. This ar ticle describes an extraordinarily objective computer algorithm for de ducing the important geometric and energetic features of the common bi nding site, starting only from the chemical structures of the ligands and their observed binding. The user does not have to propose a pharma cophore, guess the bioactive conformations of the ligands, or suggest ways to superimpose the active compounds. The method takes into accoun t conformational flexibility of the ligands, stereospecific binding, d iverse or unrelated chemical structures, inaccurate or qualitative bin ding data, and the possibility that chemically similar ligands may or may not bind to the receptor in similar orientations. The resulting mo del can be viewed graphically and interpreted in terms of: one or more binding regions of the receptor, each preferring to be occupied by va rious sorts of chemical groups. The model always fits the given data c ompletely and can predict the binding of any other ligand, regardless of chemical structure. The method is an outgrowth of distance geometry and Voronoi polyhedra site modeling but Incorporates several novel fe atures. The geometry of the ligand molecules and the site is described in terms of intervals of internal distances. Determining the site mod el consists of reducing the uncertainty in the interregion distance in tervals, and this uncertainty is described as intervals of intervals. Similarly, the given binding affinities and their experimental uncerta inties are treated as intervals in the affinity scale. The final site model specifies an entire region of interaction energy parameters that satisfy the training set rather than a single set of parameters. Pred icted binding for test compounds results in an interval which, when co mpared to the experimental interval, may be correct, incorrect, or vag ue. There is a pervasive ternary logic involved in the assessment of p redictions, in the search for a satisfactory model, and in judging whe ther a given molecule may bind in a particular orientation: true, fals e, or maybe. The approach is illustrated on an extremely simple artifi cial example and on a real data set of cocaine analogues binding to a nerve membrane receptor in vitro. (C) 1995 by John Wiley and Sons, Inc .