Development of pharmacophore and comfa study of rigid and flexible sigma 2 receptor ligands
Department of Chemistry and Environmental Science
Master of Science
Gund, Tamara M.
Venanzi, Carol A.
Bozzelli, Joseph W.
Flexible sigma 2 receptor ligands
In the present study a pharmacophore and CoMFA model was derived for sigma 2 (62) receptors by using Sybyl 7.2 Software Package. The CoMFA studies used 22 bioactive molecules as a training set and 4 molecules as a test set for the o2 receptor ligands. The geometries and electrostatic charges of all molecules were calculated using various levels of calculations. The geometry optimization and electrostatic charges of all 26 molecules were performed by using semiemprical AM1, ab initio HF/6-31G* and density functional B3LYP/6-31G* in Gaussian 98. The pharmacophore model was derived by using Distance Comparisions (DISCOtech) from 4 partially to highly active 62 receptor ligands. The Comparative Molecular Field Analysis (CoMFA) was developed for 22 bioactive 62 receptor ligands to investigate a three dimensional quantitative structural activity relationship (3D-QSAR) model for 62 receptor ligands. Three CoMFA maps were developed to compare the electrostatic and steric properties of each calculation and molecule. The best CoMFA results were obtained by using a training set of 22 molecules (R2 = 0.999) from B3LYP/6-31G*. The "leave-one-out" cross validation method gave (q2 = 0.602) using four optimal components with optimized geometries and atomic charges. This analysis produced a standard error of estimate of 0.028. The CoMFA results derived from the B3LYP/6-31G* method were better than those from AM1.
njit-etd2010-009 (44 pages ~ 2,100 KB pdf)
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Created February 4, 2011