Pharmacophore derivation using discotech and comparison of semi-emperical, AB initio and density functional CoMFA studies for sigma 1 and sigma 2 receptor-ligands

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 [H^3 ](+) 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 [H^3](+)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.

Name thesis:degree_name

Doctor of Philosophy in Chemistry - (Ph.D.)

Discipline thesis:degree_discipline

Chemistry and Environmental Science

Year

2003

Author dc:creator

• Jung, Dawoon

Contributors dc:contributor

• Tamara M. Gund
• Carol A. Venanzi
• Barbara B. Kebbekus

• QSAR
• density functional
• pharmacophore
• AB initio
• CoMFA
• sigma receptor-ligands
• Chemistry

Repository record dc:identifier

https://digitalcommons.njit.edu/dissertations/578

OAI identifier oai:identifier

oai:digitalcommons.njit.edu:dissertations-1633