Defense Date

7-25-2014

Graduation Date

2014

Availability

Immediate Access

Submission Type

thesis

Degree Name

MS

Department

Pharmacology

School

School of Pharmacy

Committee Chair

Christopher K Surratt

Committee Member

Christopher K Surratt

Committee Member

Jeffry D Madura

Committee Member

Rehana K Leak

Keywords

de novo fragment drug design, scaffold replacement, dopamine D3 receptor, ligand building, MedChem transformation

Abstract

Computational methods in drug discovery reduce research time and costs, and only now can be applied to certain psychiatric conditions due to recent breakthroughs in determining the 3D structures of relevant drug receptors in the brain. A new computational technique, de novo fragment-based drug design (DFDD), was evaluated employing a dopamine D3 receptor (D3R) crystal structure. Three DFDD approaches - scaffold replacement, ligand building, and MedChem Transformations - were assessed in replacing structural portions of eticlopride, a D2/D3R-specific antagonist, to generate compounds of novel drug scaffold. Pharmacological characterization of the compounds determined their binding affinities at target brain receptors. Analogs of scaffold replacement-generated compounds displayed moderate D3R affinity, suggesting that this DFDD method could be an important drug design tool. The findings support the addition of in silico approaches to conventional drug discovery, toward creation of new therapeutics for depression, anxiety, schizophrenia, addiction and other disorders of the central nervous system.

Format

PDF

Language

English

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