Advanced Protein Modeling Method: Benchmarking and Applications in Computer-Aided Drug Discovery

Author

Sharangdhar S. Phatak, University of Texas Health Science Center at Houston

Graduation Date

Spring 5-3-2012

Degree Name

Doctor of Philosophy (PhD)

School Name

The University of Texas School of Biomedical Informatics at Houston

Advisory Committee

Dr. Jack Smith

Abstract

Development of homology modeling methods will remain an area of active research. These methods aim to develop and model increasingly accurate three-dimensional structures of yet uncrystallized therapeutically relevant proteins e.g. Class A G-Protein Coupled Receptors. Incorporating protein flexibility is one way to achieve this goal. Here, I will discuss the enhancement and validation of the ligand-steered modeling, originally developed by Dr. Claudio Cavasotto, via cross modeling of the newly crystallized GPCR structures. This method uses known ligands and known experimental information to optimize relevant protein binding sites by incorporating protein flexibility. The ligand-steered models were able to model, reasonably reproduce binding sites and the co-crystallized native ligand poses of the β₂ adrenergic and Adenosine 2A receptors using a single template structure. They also performed better than the choice of template, and crude models in a small scale high-throughput docking experiments and compound selectivity studies. Next, the application of this method to develop high-quality homology models of Cannabinoid Receptor 2, an emerging non-psychotic pain management target, is discussed. These models were validated by their ability to rationalize structure activity relationship data of two, inverse agonist and agonist, series of compounds. The method was also applied to improve the virtual screening performance of the β₂ adrenergic crystal structure by optimizing the binding site using β₂ specific compounds. These results show the feasibility of optimizing only the pharmacologically relevant protein binding sites and applicability to structure-based drug design projects.

Recommended Citation

Phatak, Sharangdhar S., "Advanced Protein Modeling Method: Benchmarking and Applications in Computer-Aided Drug Discovery" (2012). Dissertations & Theses (Open Access). 25.
https://digitalcommons.library.tmc.edu/uthshis_dissertations/25

Keywords

Ligand-steered Modeling Method, Protein Flexibility, High Throughput Docking (HTD)