Three-dimensional quantitative structure–activity relationship for several bioactive peptides searched by a convex hull–comparative molecular field analysis approach

Three-dimensional (3D) convex hulls are computed for theoretically generated structures of a group of 18 bioactive tachykinin peptides. The number of peptides treated as a training set is 14, whereas that treated as a test set is four. The frequency of atoms of the same atomic type lying at the vertices of all the hulls computed for all the structures in a structural set is counted. Vertex atoms with non-zero frequency counted are collected together as a set of commonly exposed groups. These commonly exposed atoms are then treated as a set of correspondences for aligning all the other 13 structures in a structural set against a common template, which is the structure of the most potent peptide in the set using the FIT module of the sybyl 6.6 program. Each aligned structural set is then analyzed by the comparative molecular field analysis (CoMFA) module using the C.3 probe having a charge of +1.0. The corresponding cross-validated r² values range from −0.99 to 0.57 for a number of 73 structural sets studied. The comparative molecular similarity indices analysis (CoMSIA) module within the sybyl 6.6 package is also used to analyze some of these aligned structural sets. Although the CoMSIA results are in accord with those of CoMFA, it is also found that the CoMFA results of several structural sets can be improved somewhat for conformations of the structures in the sets that are adjusted by constraint energy minimization and then constraint molecular dynamics simulation runs using distance constraints derived from some commonly exposed groups determined for them. This result further implies that the convex hull–CoMFA is a feasible approach to screen the bioactive conformations for molecules of this class.