Virtual screening of small molecule inhibitors towards the tumor suppressor p53 to overcome radioresistance of nasopharyngeal carcinoma cells

Publication type:
Conference
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000209823902139&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1158/1538-7445.AM10-2679
eISSN
1538-7445
Externe Identifier
  • Clarivate Analytics Document Solution ID: V45NS
ISSN
0008-5472
Zeitschrift
CANCER RESEARCH
Datum der Veröffentlichung
2010
Status
Published
Titel
Virtual screening of small molecule inhibitors towards the tumor suppressor p53 to overcome radioresistance of nasopharyngeal carcinoma cells
Ausgabe der Zeitschrift
70

Data source: Web of Science (Lite)

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Abstract
<jats:title>Abstract</jats:title> <jats:p>The tumor suppressor p53 belongs to the most frequently mutated genes in cancer, including nasopharyngeal carcinoma (NPC). p53 is over-expressed in NPC, but the mutation rate is lower than in other tumor types. Therefore, it can be hypothesized that p53 might be involved in repair of DNA-damage after radiotherapy and causes recrudescence. Hence, the aim of the present investigation was to identify small molecule inhibitors for p53 to inhibit DNA repair after ionizing radiation of NPC.</jats:p> <jats:p>Approximately 260.000 2D-structures from NCI database were downloaded and different tautomers and charged stages between pH 5 and 9 were calculated for each compound. A total number of 906.587 drugs in different 3D-conformations have been generated for our virtual screening approach. By means of the Glide software and three-dimensional p53 structure based on the published crystal structure 1TUP from PDB database, 25 compounds have been identified as candidates to bind to the DNA-binding domain of p53. The best evaluated ligand (consisting 26 atoms) had the assigned binding energy of −8.41 kcal mol-1 in Glide. This outstanding binding was confirmed by using AutoDock which has result in −10.57 kcal mol-1. In comparison, the binding of PRIMA-1 as experimentally validated drug showed a binding energy of −6.30 kcal mol-1 after blind docking procedure with subsequent refinement.</jats:p> <jats:p>As a next step, the compounds identified in silico have been experimentally verified in vitro by means of Plasmon resonance spectroscopy. To prove, whether inhibition of DNA-binding of p53 by these small molecule inhibitors affect the response of the NPC cell line CNE1 towards ionizing radiation, the cytotoxicity of 0.5 – 16 Gy has been measured with and without addition of these small molecule inhibitors by XTT assays. Indeed, the addition of some of the identified candidate compounds were able to increase the cytotoxic effects of ionizing radiation.</jats:p> <jats:p>The present investigation indicates that the combination of ionizing radiation with novel small molecule inhibitors for p53 increased the killing rate of CNE1 cells. These data may have important implications for radiochemotherapy of NPC in the future.</jats:p> <jats:p>Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2679.</jats:p>
Autoren
DOI
10.1158/1538-7445.am10-2679
eISSN
1538-7445
ISSN
0008-5472
Ausgabe der Veröffentlichung
8_Supplement
Zeitschrift
Cancer Research
Paginierung
2679 - 2679
Datum der Veröffentlichung
2010
Status
Published
Herausgeber
American Association for Cancer Research (AACR)
Herausgeber URL
http://dx.doi.org/10.1158/1538-7445.am10-2679
Datum der Datenerfassung
2022
Titel
Abstract 2679: Virtual screening of small molecule inhibitors towards the tumor suppressor p53 to overcome radioresistance of nasopharyngeal carcinoma cells
Ausgabe der Zeitschrift
70

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