Improved alignment by weighted field fit in CoMFA of histamine H-2 receptor agonists imidazolylpropylguanidines

More realistic description of ligand-receptor interactions in CoMFA results from alignments considering surface and field properties instead of only m olecular frameworks. The field fit algorithm implemented in SYBYL (Tripos A ss.) as part of:the energy minimizer provides the possibility to assign ind ividual weights to grid points. A new weighting function derives the signif icance of grid points for the alignment of fields from preceding CoMFA runs , using regression coefficients, means, and standard deviations of field:va riables as parameters. Just in strongly diverse congeneric series, the meth od does not underestimate the common structure and not overweight variable, interacting regions. CoMFA of a large series of 142 histamine H-2 receptor agonistic imidazolylpropylguanidines (pD(2) values from guinea pig atrium) is presented as example. Results with three different alignments were comp ared: (1) exact superposition of the constant imidazolylpropylguanidine moi ety, (2) SUPERIMPOSE or FIT of energy minima, (3) minimization of the struc tures by weighted field fit with weights based on CoMFA with alignment 2. A significant improvement of cross-validated PLS results was observed from a lignment to alignment: Leave-one-out approach: (1) 7 PC's, Q(2)=0.59, S-PRE SS=0.50, (2) 8 PC's, Q(2)=0.66, S-PRESS = 0.46, (3) 9 PC's, Q(2) = 0.71, S- PRESS = 0.42. Cross validation with 10 groups (mean of 10 runs): (1) 6.3 PC 's, Q(2) = 0.59, S-PRESS = 0.50, (2) 6.1 PC's, Q(2) = 0.65, S-PRESS = 0.47, (3) 9.5 PC's, Q(2) = 0.71, S-PRESS = 0.43. It is concluded that risks of t he field fit method like producing artificial redundancy of the structures and ignoring entropy contributions to the free energy of binding are lowere d with the given weighting method.