A FAST AND EFFICIENT METHOD TO GENERATE BIOLOGICALLY RELEVANT CONFORMATIONS

Mutual binding between a ligand of low molecular weight and its macrom olecular receptor demands structural complementarity of both species a t the recognition site. To predict binding properties of new molecules before synthesis, information about possible conformations of drug mo lecules at the active site is required, especially if the 3D structure of the receptor is not known. The statistical analysis of small-molec ule crystal data allows one to elucidate conformational preferences of molecular fragments and accordingly to compile libraries of putative ligand conformations. A comparison of geometries adopted by correspond ing fragments in ligands bound to proteins shows similar distributions in conformation space. We have developed an automatic procedure that generates different conformers of a given ligand. The entire molecule is decomposed into its individual ring and open-chain torsional fragme nts, each used in a variety of favorable conformations. The latter one s are produced according to the library information about conformation al preferences. During this building process, an extensive energy rank ing is applied. Conformers ranked as energetically favorable are subje cted to an optimization in torsion angle space. During minimization, u nfavorable van der Waals interactions are removed while keeping the op en-chain torsion angles as close as possible to the experimentally mos t frequently observed values. In order to assess how well the generate d conformers map conformation space, a comparison with experimental da ta has been performed. This comparison gives some confidence in the ef ficiency and completeness of this approach. For some ligands that had been structurally characterized by protein crystallography, the progra m was used to generate sets of some 10 to 100 conformers. Among these, geometries are found that fall convincingly close to the conformation s actually adopted by these ligands at the binding site.