Type
Text
Type
Dissertation
Advisor
Rizzo, Robert C | Deng, Yuefan | Green, David F | Rudick, Jonathan.
Date
2015-12-01
Keywords
computational biology, drug design, free energy calculation, HIVgp41, molecular docking, molecular modeling | Applied mathematics
Department
Department of Applied Mathematics and Statistics.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/77732
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
This dissertation presents method development and application of computational procedures for structure-based drug design, with a particular focus on the clinical relevant drug target HIVgp41. Chapter 1 introduces the main computational techniques used in this study, including atomic-level molecular dynamics simulations, free energy calculations, and molecular docking. The importance of targeting HIVgp41, a viral envelope protein involved in viral entry and membrane fusion, is also discussed. In particular, the only FDA approved gp41 inhibitor, a peptide called T20, suffers from side effects, expense, and is subject to drug resistance. Thus, improved understanding of the binding mechanisms of T20 is of great interest, which provides the motivation for the computational work in this dissertation. Chapter 2 describes a newly implemented DOCK scoring function termed pharmacophore matching similarity (FMS) score. By matching pharmacophore features in references, such as those in known peptide inhibitors of gp41, FMS score can help guide docking of small molecules to yield hits with desired properties. This new DOCK method, when used alone (FMS) and in combination with the standard single grid energy score (FMS+SGE), is validated via pose reproduction, crossdocking and enrichment studies with desirable outcomes using large molecular docking testsets. Chapter 3 presents additional in-depth analyses of the FMS case studies for enrichment, as well as post-processing of virtual screening results targeting both the gp41 hydrophobic and inner pockets. Chapter 4 presents preliminary applications of FMS score for de novo design using small (focused) fragment libraries generated for 50 small molecule test cases as well as peptide test cases targeting the two gp41 pockets. Chapter 5 reports molecular dynamics simulation and free energy calculation results for T20 in complex with gp41 (T20-gp41) to help characterize the biological effects of a series of primary and secondary mutations. Per-residue energetic analyses and structural characterization of end-point simulations were employed to identify key residues at the T20-gp41 binding interface. Importantly, good agreement with experimental activity trends was observed for a series of T20 analogs with three gp41 variants, using a thermodynamic integration protocol, which further supports the atomistic model. Chapter 6 summarizes the work presented in the dissertation in terms of scientific impact, challenges, and future studies to further aid structure-based drug design targeting HIVgp41. | 199 pages
Recommended Citation
Jiang, Lingling, "Structure-Based Drug Design Targeting HIVgp41" (2015). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 3519.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/3519