Inhibitor Studies for 5’-ecto-nucleotidase (CD73)
| Main Author: | |
|---|---|
| Language: | English |
| Published: |
Ohio University / OhioLINK
2019
|
| Subjects: | |
| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1553892946798977 |
| id |
ndltd-OhioLink-oai-etd.ohiolink.edu-ohiou1553892946798977 |
|---|---|
| record_format |
oai_dc |
| spelling |
ndltd-OhioLink-oai-etd.ohiolink.edu-ohiou15538929467989772021-08-03T07:09:47Z Inhibitor Studies for 5’-ecto-nucleotidase (CD73) Roever, Lisa Biochemistry Chemistry Inhibitor Studies drug discovery inhibitor leads Computational studies are a powerful tool in drug discovery. They are used to predict protein-ligand interactions. High throughput virtual screening aids to select potent molecules out of large databases. This method was applied to the enzyme ecto-5`- nucleotidase (CD73) that dephosphorylates extracellular AMP to adenosine. CD73 plays a key role in the regulation of extracellular purinergic signaling, since it represents the major control point for the extracellular adenosine level. It is a promising drug target in inflammation, chronic pain, hypoxia and cancer. This work aims to find inhibitor leads of CD73 via docking. The active site and two allosteric sites were addressed. Targeted libraries were docked to the active site and diversity and natural product libraries were screened for binders to allosteric sites. Docking was validated by two methods. First, compounds with known binding parameters were docked. GlideScores as a measure of binding between the ligand and CD73 and the respective Ki values of the compounds do not correlate. This can be explained by insufficient modelling of waters. Second, nine ligands that were previously cocrystallized along with CD73 were docked to two different hydration states and their atom RMSD values compared. 50 % of those compounds align with their respective atom positions derived from crystallography at RMSD values below 2 Å. Four compounds were selected for subsequent experiments based on the library scans. CT-115, AC-1402 and PR-119 are members of the phosphatase library and were docked to the active site. Allantoin bound to the allosteric site around the hinge region between the two domains of CD73 in silico. Ki and vmax values of those compounds were determined experimentally. CT-115 and AC-1402 inhibit CD73 at Ki values in the nanomolar range and PR-119 in the micromolar range, respectively. Allantoin does not inhibit CD73. The three inhibiting compounds CT-115, AC-1402 or PR 119 were cocrystallized with CD73; the electron densities did not allow for modeling of the molecules. 2019-06-13 English text Ohio University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1553892946798977 http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1553892946798977 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biochemistry Chemistry Inhibitor Studies drug discovery inhibitor leads |
| spellingShingle |
Biochemistry Chemistry Inhibitor Studies drug discovery inhibitor leads Roever, Lisa Inhibitor Studies for 5’-ecto-nucleotidase (CD73) |
| author |
Roever, Lisa |
| author_facet |
Roever, Lisa |
| author_sort |
Roever, Lisa |
| title |
Inhibitor Studies for 5’-ecto-nucleotidase (CD73) |
| title_short |
Inhibitor Studies for 5’-ecto-nucleotidase (CD73) |
| title_full |
Inhibitor Studies for 5’-ecto-nucleotidase (CD73) |
| title_fullStr |
Inhibitor Studies for 5’-ecto-nucleotidase (CD73) |
| title_full_unstemmed |
Inhibitor Studies for 5’-ecto-nucleotidase (CD73) |
| title_sort |
inhibitor studies for 5’-ecto-nucleotidase (cd73) |
| publisher |
Ohio University / OhioLINK |
| publishDate |
2019 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1553892946798977 |
| work_keys_str_mv |
AT roeverlisa inhibitorstudiesfor5ectonucleotidasecd73 |
| _version_ |
1719454873404047360 |