Development of pharmacophore and CoMFA studies for sigma2 receptor ligands

Author

Laura Ann Wirpsza, New Jersey Institute of Technology

Document Type

Thesis

Date of Award

Summer 8-31-2008

Degree Name

Master of Science in Chemistry - (M.S.)

Department

Chemistry and Environmental Science

First Advisor

Tamara M. Gund

Second Advisor

Carol A. Venanzi

Third Advisor

Joseph W. Bozzelli

Abstract

This study describes the development of a pharmacophore and CoMIFA model for sigma 2 (σ₂) receptor ligands. CoMFA studies were performed for 32 bioactive σ₂ receptor ligands using the radioligand [H 3] (+) DTG in the presence of pentazocine. The pharmacophore was derived using Distance Comparisons (DISCOtech) from eight partially to highly active ~2 receptor ligands. All 32 compounds were calculated in three methods: AMi, HFI3~21G*, and B3LYP/3~21G* methods. These methods run in Gaussian 98 determined the geometry optimization and electrostatic charges for each molecule. CoMFA maps were developed using SYBYL ver. 7.2 to compare the electrostatic and steric properties of each calculation and molecule. With "leave-one-out" cross validation, the numbers of optimal components was determined. No cross validation was performed in a training set using the optimal components for each analysis. After the completion of a test set, it was verified that CoMIFA models derived from HF/3~21G* optimized geometries and atomic charges are more reliable in predicting the bioactivities of σ₂ receptor ligands. Using the HF/3~21G* analysis, new active σ₂ receptor ligands were designed and pK i values were predicted. It was determined that active σ₂ receptor ligands require localization on the benzene ring contributed through an electron withdrawing group.

Recommended Citation

Wirpsza, Laura Ann, "Development of pharmacophore and CoMFA studies for sigma2 receptor ligands" (2008). Theses. 370.
https://digitalcommons.njit.edu/theses/370