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The Impact of Allosteric Modulators on The Orthosteric and Allosteric Binding Pockets

Chen, Chih-Jung (2022) The Impact of Allosteric Modulators on The Orthosteric and Allosteric Binding Pockets. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Allosteric modulators (AM) that bind allosteric sites can exhibit greater selectivity than the orthosteric ligands and can either enhance agonist-induced receptor activity (termed positive allosteric modulator, or PAM), inhibit agonist-induced activity (negative AM, or NAM), or have no effect on activity (silent AM, or SAM). Until now, it is not clear what the exact effects of AMs are on the orthosteric active site or the allosteric binding pocket(s). In the present work, we collected both the 3D structures of receptor-orthosteric ligand and receptor-orthosteric ligand-AM complexes of a specific target protein. Using our novel algorithm toolset-Molecular Complex Characterizing System (MCCS), we were able to quantify the key residues in both the orthosteric and allosteric binding sites along with potential changes of the binding pockets. After analyzing 21 pairs of 3D crystal or cryo-EM complexes, including 4 pairs of GPCRs, 5 pairs of ion channels, 11 pairs of enzymes, and 1 pair of transcription factors, we found that the binding of AMs had little impact on both the orthosteric- and allosteric- binding pockets. In return, given the accurately predicted allosteric binding pocket(s) on a drug target of medicinal interest, we can confidently conduct the virtual screening or lead optimization without concern that the huge conformational change of the pocket could lead to the low accuracy of virtual screening.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Chen, Chih-Jungchc327@pitt.educhc327
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKirisci, Leventlevent@pitt.edu
Committee CoChairWang, Junmeijunmei.wang@pitt.edu
Committee MemberXie, Xiang-QunSean.Xie@pitt.edu
Committee MemberFeng, Zhiweizhf11@pitt.edu
Thesis AdvisorFeng, Zhiweizhf11@pitt.edu
Date: 6 April 2022
Date Type: Publication
Defense Date: 23 March 2022
Approval Date: 6 April 2022
Submission Date: 29 March 2022
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 74
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: Allosteric modulator, MCCS, drug discovery
Date Deposited: 29 Aug 2022 20:20
Last Modified: 29 Aug 2022 20:20
URI: http://d-scholarship.pitt.edu/id/eprint/42630

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