A comparative molecular field analysis (CoMFA) study using semiempirical, density functional, ab initio methods and pharmacophore derivation using DISCOtech on sigma 1 ligands

The Comparative Molecular Field Analysis (CoMFA) was developed to investigate a three‐dimensional quantitative structure activity relationship (3D‐QSAR) model of ligands for the sigma 1 receptor. The starting geometry of sigma‐1 receptor ligands was obtained from the Tripos force field minimizations and conformations were decided from DISCOtech using the SYBYL 6.8. program. The structures of 48 molecules were fully optimized at the ab initio HF/3‐21G* and semiempirical AM1 calculations using GAUSSIAN 98. The electrostatic charges were calculated using several methods such as semiempirical AM1, density functional B3LYP/3‐21G*, and ab initio HF/3‐21G*, MP2/3‐21G* calculations within GAUSSIAN 98. Using the optimized geometries, the CoMFA results derived from the HF/3‐21G method were better than those from AM1. The best CoMFA was obtained from HF/3‐21G* optimized geometry and charges (R² = 0.977). Using the optimized geometries, the CoMFA results derived from the HF/3‐21G methods were better than those from AM1 calculations. The training set of 43 molecules gave higher R² (0.989–0.977) from HF/3‐21G* optimized geometries than R² (0.966–0.911) values from AM1 optimized geometries. The test set of five molecules also suggested that HF/3‐21G* optimized geometries produced good CoMFA models to predict bioactivity of sigma 1 receptor ligands but AM1 optimized geometries failed to predict reasonable bioactivity of sigma 1 receptor ligands using different calculations for atomic charges. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1385–1399, 2004