Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Molecular Modeling Study of Receptor-Orthosteric Ligand-Allosteric Modulator Signaling Complex

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 (Unpublished)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.

[img] PDF
Accepted Version
Restricted to University of Pittsburgh users only until 6 April 2024.

Download (3MB) | Request a Copy


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.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Jiang, Chenchj51@pitt.eduCHJ510000000183366814
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWang, Junmeijuw79@pitt.edu0000-0002-9607-8229
Committee CoChairKirisci,
Committee MemberXie,
Committee MemberFeng,
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 2022 13:47

Available Versions of this Item


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item