DIRECT PREDICTION OF LINEAR FREE ENERGY SUBSTITUENT EFFECTS FROM 3D STRUCTURES USING COMPARATIVE MOLECULAR FIELD ANALYSIS. I, ELECTRONIC EFFECTS OF SU BSTITUTED BENZOIC ACIDS

We examined the ability of the comparative molecular field analysis (CoMFA) method to reproduce Hammett σ constants. The dataset includes 49 substituted benzoic acids. Molecular fields calculated with an H + probe and AM1 partial atomic charges produce a good fit and cross-validated estimate of σ. This estimate is more accurate than that found from a CoMFA analysis using charges based on fits to STO-3G electrostatic potential surfaces. It is also superior to that derived from regression analysis of the charges on the atoms. The relationships predicted the σ of 21 of 23 additional compounds to within 0.27 kcal/mol. We concluded that the CoMFA treatment of electrostatic effects is suitable for the examination of 3D quantitative structure-bioactivity relationships