Jiang, Chen
(2022)
Molecular Modeling Study of Receptor-Orthosteric Ligand-Allosteric Modulator Signaling Complex.
Master's Thesis, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Allosteric modulators (AMs) are always the hotspot in research for their higher selectivity and various effects on the orthosteric ligands (OL), whereas AMs are also classified in terms of its functionalities as positive, negative, or silent allosteric modulators (PAM, NAM or SAM, resprctively). In the present work, 11 pairs of the 3D structures of receptor-orthosteric ligand or receptor-orthosteric ligand-allosteric modulator complexes are collected for the studies, which belong to 3 different systems: GPCR, Enzyme and Ion Channel. MD simulation is applied to quantify and visualize the dynamic interactions in the orthosteric and allosteric binding pockets and structural fluctuation of proteins. Our results showed that MD simulations of moderately large molecules or peptides undergo insignificant change compared to crystal structures' results. However, due to the flexibility of small molecules like glutamate, the results of the post-MD analysis and MMGBSA binding free energy on receptor and small molecule may be altered. Furthermore, we also studied the conformational changes of receptors that bound with PAM and NAM, as well as the different allosteric binding sites in a receptor. It seems that there should be no preference for the position of the allosteric binding pocket after comparing the allosteric binding pockets of these three systems. Finally, we aligned four distinct β2 adrenoceptor structures and three NMDAR structures to investigate conformational changes. In the β2 adrenoceptor system, the aligned results revealed that TMs 1, 5 and 6 gradually increased outward movement from an enhanced inactive state to an improved active state. TM 6 endured the most significant conformational change (around 11 Å). For NMDAR, the orthosteric binding sites experienced an outward and downward shift during the gradually activating process. In conclusion, our research provides insights for receptor-orthosteric ligand-allosteric modulator studies and the design and development of allosteric modulator drugs by using MD simulation.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
6 April 2022 |
| Date Type: |
Publication |
| Defense Date: |
22 March 2022 |
| Approval Date: |
6 April 2022 |
| Submission Date: |
4 April 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
79 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
MD simulation, Orthosteric binding pocket, Allosteric modulator, β2 adrenoceptor |
| Date Deposited: |
06 Apr 2022 13:47 |
| Last Modified: |
06 Apr 2024 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42497 |
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