Pharmacophore derivation using discotech and comparison of semi-emperical, AB initio and density functional CoMFA studies for sigma 1 and sigma 2 receptor-ligands
Department of Chemistry and Environmental Science
Doctor of Philosophy
Gund, Tamara M.
Venanzi, Carol A.
Kebbekus, Barbara B.
Malhotra, Sanjay V.
Van Dyke, Christopher C.
This study describes the development of pharmacophore and CoMFA models for sigma receptor ligands. CoMFA studies were performed for 48 bioactive sigma 1 receptorligands using [H3 ](+) pentazocine as the radioligand, for 30 PCP derivatives for sigma 1 receptor-ligands using [3H](+)SK-F 10047 as the radioligand and for 24 bioactive sigma 2 receptor-ligands using the radioligand [H3](+)DTG in the presence of pentazocine. Distance Comparisons (DISCOtech) was used as the starting point for CoMFA studies. The conformers, derived by DISCOtech were optimized using AMi, or HF/3-21G* in Gaussian 98. The optimized geometries were aligned with the pharmacophore, derived using DISCOtech. Atomic charges were calculated using AMl, HF/3-21G*, B3LYP/3-21G*, MP2/3-21G* methods in Gaussian 98. The CoMFA Maps that were developed using Sybyl 6.9 were compared on steric and electrostatic field differences. With leaveone-out cross validation the numbers of optimal components were decided. Using these numbers of optimal components no cross validation was performed in a training set. After a test set, it was known that CoMFA models derived from HF/3-21G* optimized geometries were more reliable in predicting bioactivities than CoMFA models derived from AMi optimized geometries.
njit-etd2003-075 (174 pages ~ 9,814 KB pdf)
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Created June 2, 2004