The New Jersey Institute of Technology's
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Title:	Molecular modeling of sigma 1 and sigma 2 receptor ligands: pharmacophore development and comparison using discotech and bioactivity prediction comparison of ab initio and density functional comfa studies for spiro and other receptor ligands
Author:	Kardos, Lisa M.
View Online:	njit-etd2015-021 (xx, 157 pages ~ 5.7 MB pdf)
Department:	Department of Chemical, Biological and Pharmaceutical Engineering
Degree:	Doctor of Philosophy
Program:	Chemical Engineering
Document Type:	Dissertation
Advisory Committee:	Gund, Tamara M. (Committee chair) Loney, Norman W. (Committee co-chair) Armenante, Piero M. (Committee member) Tomkins, R. P. T. (Committee member) Migdal, Cyril A. (Committee member)
Date:	2015-01
Keywords:	Sigma 1 Sigma 2 COMFA Pharmacophore Bioactivity prediction Receptor ligand
Availability:	Unrestricted
Abstract:	The role of the biological receptor is currently being studied by researchers in medicine. Information about sigma receptors in particular can be gained by studying the ligands associated with each type, sigma 1 or sigma 2. Sigma 1 receptor ligands consist of drug candidates that often have psychiatric and neurological applications; sigma 2 receptor ligands consist of drug candidates that have been linked with cancer treatment among other applications. Molecular modeling of biological receptor ligands often encompasses pharmacophore development and Comparative Molecular Field Analysis (CoMFA). Pharmacophore models are developed to understand the unique features such as binding groups that make a ligand bioactive. CoMFA uses experimental data of molecules, considered to be a training set, to yield bioactivity prediction for those molecules; this is the internal validation piece. An external test set of molecules with known experimental data can then be used for validation of the CoMFA models. The resulting CoMFA models create contour maps which provide information about the sterics and electrostatics, resulting in the ability to apply this information during the design of new ligands. The new molecules can then be tested in the validated CoMFA models to yield bioactivity predictions. This study describes the development of pharmacophore and Comparative Molecular Field Analysis (CoMFA) models for sigma 1 and sigma 2 receptor ligands. Distance Comparisons (DISCOtech) in SYBYL-X 2.1 is used as a tool for the pharmacophore development. A pharmacophore is developed for each individual class of molecules and for the entire set of sigma 1 molecules and sigma 2 molecules analyzed during this study, respectively. All compounds are calculated in SPARTAN ’14 using ab initio and density functional calculation methods H F/6-31 G* and B3LY P/6-31 G* prior to model development. These calculations determine the geometry optimization and electrostatic charges for each molecule. CoM FA studies, utilizing SY BY L-X 2. 1, are performed for 41 sigma 1 receptor l igands using the radiol igand [ H 3] (+) pentazoci ne and for 31 sigma 2 receptor l igands using [ H 3] (+) DTG in the presence of pentazoci ne. The CoMFA models developed confirm that bioactivity prediction comparison is reliable for both H F/6-31 G* and B3LYP/6-31G* optimized geometries for both sigma 1 and sigma 2 ligands; this is verified via both internal and external validation methods. The CoMFA contour maps are utilized to design new sigma 1 and sigma 2 l igands; the newly designed l igands are predicted to be highly active according to the CoMFA models. This study also compares CoMFA models between the ab initio and density functional calculation levels for sigma 1 and sigma 2 ligands, respectively. The similarities and differences between sigma 1 and sigma 2 receptor l igands are also analyzed via the developed pharmacophore models and generated CoM FA contour maps.