Date of Degree

2-2019

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Thomas P. Kurtzman

Committee Members

Ian Alberts

Daniel McKay

Gustavo Lopez

Wayne Harding

Subject Categories

Biochemistry | Physical Chemistry | Structural Biology

Keywords

Solvation Thermodynamic Mapping, Computer-Aided Drug-Design, Molecular Modeling

Abstract

The displacement of water from surfaces upon biomolecular recognition and association makes a significant contribution to the free energy changes of these processes. We therefore posit that accurate characterization of local structural and thermodynamic molecular water properties can improve computational model accuracy and predictivity of recognition and association processes. In this thesis, we discuss Solvation Thermodynamic Mapping (STM) methods that we have developed using inhomogeneous fluid solvation theory (IST) to better characterize active site water structural and thermodynamic properties on protein surfaces and the open source tools that we have developed, GIST-CPPTRAJ and SSTMap, which implement these methods which we have distributed to both the academic and industrial scientific community. These methods include a nearest neighbor approximation for water entropies, a significant improvement over previous entropy formulations. We then discuss our application of these tools to the rational modification of (-)-stepholidine, a lead compound for human dopamine receptor 3 (D3R), which led to a handful of promising analogues. Finally, we describe a new method of creating pharmacophores from solvation thermodynamic maps applied retrospectively to 7 protein targets. The results documented here demonstrate promising applications of STM methods for prospective drug design. In our conclusions, we discuss potential improvements to the molecular modeling work with the goal of improving accuracy of predictions in prospective drug design projects.

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