Alignment of molecules by weighted field fit considering active shape

Abstract

A systematic investigation of the advantages, drawbacks, and rules of the new weighted field fit method was presented and compared with other weighting approaches. The TAPA training and test series of benzamide type trypsin, thrombin, and factor Xa inhibitors, whose original alignment roughly reflects a common binding site of the three serine proteases, provide sufficient data for this goal. Field fits weighted by |MEANs|× |COEFF|/SDEV consider the "active shape" as ref. for the alignment of mols., improve CoMFA models best and generate the lowest energies, if a highly potent compd. without unfavorable bulk is utilized as template. "Soft" field fits are commonly most suitable and the improvement of q2 appears to be limited to less than 20%. The method can make the most of the potential of a 3D-QSAR anal. if carefully used.