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

Three-dimensional (3D) convex hulls are computed for theoretically generate d 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 se t is four. The frequency of atoms of the same atomic type lying at the vert ices of all the hulls computed for all the structures in a structural set i s counted. Vertex atoms with non-zero frequency counted are collected toget her as a set of commonly exposed groups. These commonly exposed atoms are t hen treated as a set of correspondences for aligning all the other 13 struc tures 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 r(2) values range from -0.99 t o 0.57 for a number of 73 structural sets studied. The comparative molecula r 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 th e CoMFA results of several structural sets can be improved somewhat for con formations of the structures in the sets that are adjusted by constraint en ergy minimization and then constraint molecular dynamics simulation runs us ing distance constraints derived from some commonly exposed groups determin ed for them. This result further implies that the convex hull-CoMFA is a fe asible approach to screen the bioactive conformations for molecules of this class. (C) 2001 Elsevier Science Ltd. All rights reserved.