Defense Date
7-25-2014
Graduation Date
Fall 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
Language
English
Recommended Citation
Hailemicael, D. (2014). In Silico-Guided Design of Novel-Scaffold Therapeutics Targeting the Dopamine D3 Receptor (Master's thesis, Duquesne University). Retrieved from https://dsc.duq.edu/etd/615