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Identifying selective ligands for glutaredoxin proteins with fragment based drug design approach and optimization of the bacterial selective hits

Khattri, Ram Bahadur
http://rave.ohiolink.edu/etdc/view?acc_num=akron1460988438

Abstract Details

2016, Doctor of Philosophy, University of Akron, Chemistry.
Fragment-Based Drug discovery (FBDD) is one of the most appealing techniques for the study of the binding interaction of fragments with putative drug target proteins. The primary aim of this study is to discover and develop medicinally significant small fragment molecules that are more selective towards bacterial antioxidant proteins, avoiding cross-reactivity with human orthologs. Glutaredoxin from three organisms, human (hGRX1), Brucella melitensis (BrmGRX) and Pseudomonas aeruginosa (PaGRX) were utilized for this study. These proteins consist of a conserve CPYC active site that serves as the soft nucleophilic thiolate site for binding warhead-based lead molecules. In the first part of this work, selectively binding fragments were identified for the bacterial proteins via three nuclear magnetic resonance (NMR) methods: Saturation transfer difference (STD) for screening a small library against three GRXs, and transfer nuclear Overhauser effect (trNOE) and 15N hetero nuclear single quantum correlation (HSQC) for positive STD hits validation. The fragments obtained via the NMR-based FBDD approach were further optimized to get more potent and reactive lead molecules. Quantitative determination of dissociation constant (Kd) and ligand efficiency for some selected hits were also performed via 2D NMR. The half-time for the reaction determined for some synthesized lead molecules against these proteins reflects the success we achieved to develop more potent and selective lead molecules. Though the effects shown by these lead molecules are subtle, this opens the door for the discovery of new compounds to synthesize drugs targeted against glutaredoxin proteins; an untapped reservoir of antibiotic agents.
Thomas Leeper, Dr. (Advisor)
Peter Rinaldi, Dr. (Committee Member)
Leah Shriver, Dr. (Committee Member)
Sailaja Paruchuri, Dr. (Committee Member)
Todd Blackledge, Dr. (Committee Member)
258 p.
Biochemistry; Chemistry
glutaredoxin, FBDD, STD, HSQC, trNOE, warhead, ortholog

Recommended Citations

Citations

  • Khattri, R. B. (2016). Identifying selective ligands for glutaredoxin proteins with fragment based drug design approach and optimization of the bacterial selective hits [Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1460988438

    APA Style (7th edition)

  • Khattri, Ram. Identifying selective ligands for glutaredoxin proteins with fragment based drug design approach and optimization of the bacterial selective hits. 2016. University of Akron, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=akron1460988438.

    MLA Style (8th edition)

  • Khattri, Ram. "Identifying selective ligands for glutaredoxin proteins with fragment based drug design approach and optimization of the bacterial selective hits." Doctoral dissertation, University of Akron, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=akron1460988438

    Chicago Manual of Style (17th edition)

akron1460988438
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© 2016, some rights reserved.Creative Commons License Identifying selective ligands for glutaredoxin proteins with fragment based drug design approach and optimization of the bacterial selective hits by Ram Bahadur Khattri is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Akron and OhioLINK.