Hellemann Holguin, Erich
(2023)
Computer-aided drug design: developing and applying simulation-based tools to identify small-molecule ligands that inhibit proteins.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
In this dissertation, I discuss how computational methods can help in drug discovery, from developing a new tool that allows obtaining ensembles of protein conformations to using established computational tools for elucidating the mechanism of inhibition.
Sub-Pocket Explorer (SubPEx) is a tool I wrote that leverages weighted ensemble to accelerate the sampling of protein pocket conformations. I demonstrated that SubPEx is faster and protein pocket conformations are more diverse than those obtained by vanilla molecular dynamics (MD) simulations. I applied the SubPEx algorithm to three relevant proteins for human health: heat shock protein 90, neuraminidase, and hexokinase II. With these proteins, I showed how SubPEx could be applied to small rigid proteins, proteins with a flexible pocket, and proteins that undergo extensive domain rearrangements.
I show how a combination of experimental and computational work can help find a new resistance mechanism to the known inhibitor 2-deoxy-glucose (2DG). I described how collaborators found a new mutation in hexokinase II and how with MD simulations, I proposed a mechanism by which this mutation could confer resistance to 2DG.
Finally, I show the importance of undergraduate research and what we can achieve with the help of undergraduates. In one of the two projects I did with undergraduates, we applied an established computational protocol to recommend small molecule binders to a protein involved in cancer. The last project I described in the dissertation is how we used MD simulations to discover the allosteric mechanism by which a small molecule inhibits TEM-1, a protein involved in multidrug resistance.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
25 January 2023 |
| Date Type: |
Publication |
| Defense Date: |
21 September 2022 |
| Approval Date: |
25 January 2023 |
| Submission Date: |
31 October 2022 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
163 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Molecular Biophysics and Structural Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Computer-aided drug design, Molecular dynamics, Weighted ensemble, docking |
| Date Deposited: |
25 Jan 2023 16:30 |
| Last Modified: |
25 Jan 2023 16:30 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43845 |
Available Versions of this Item
-
Computer-aided drug design: developing and applying simulation-based tools to identify small-molecule ligands that inhibit proteins. (deposited 25 Jan 2023 16:30)
[Currently Displayed]
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}