Next Article in Journal
Geranylgeranylacetone Ameliorates Intestinal Radiation Toxicity by Preventing Endothelial Cell Dysfunction
Previous Article in Journal
miR-425-5p Inhibits Differentiation and Proliferation in Porcine Intramuscular Preadipocytes
Previous Article in Special Issue
Proteome Stability as a Key Factor of Genome Integrity
Article Menu

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2017, 18(10), 2102; doi:10.3390/ijms18102102

Combined Virtual and Experimental Screening for CK1 Inhibitors Identifies a Modulator of p53 and Reveals Important Aspects of in Silico Screening Performance

1
Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens, Greece
2
Protein Phosphorylation & Human Disease Group, Station Biologique, B. P. 74, CEDEX 29682 Roscoff, Bretagne, France
3
ProtATonce Ltd., 15343 Athens, Greece
4
School of Mechanical Engineering, National Technical University of Athens, 15780 Athens, Greece
5
ManRos Therapeutics, Perharidy Research Center, Roscoff, 29680 Bretagne, France
6
Department of Histology-Embryology, School of Medicine, University of Athens, Mikras Asias 75, GR-11527 Athens, Greece
7
Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
8
Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, M13 9NT Manchester, UK
9
“Athena” Research and Innovation Center, 15125 Athens, Greece
*
Authors to whom correspondence should be addressed.
Received: 1 September 2017 / Revised: 25 September 2017 / Accepted: 3 October 2017 / Published: 6 October 2017
(This article belongs to the Special Issue Mechanisms Leading to Genomic Instability)
View Full-Text   |   Download PDF [2024 KB, uploaded 6 October 2017]   |  

Abstract

A compound collection of pronounced structural diversity was comprehensively screened for inhibitors of the DNA damage-related kinase CK1. The collection was evaluated in vitro. A potent and selective CK1 inhibitor was discovered and its capacity to modulate the endogenous levels of the CK1-regulated tumor suppressor p53 was demonstrated in cancer cell lines. Administration of 10 μM of the compound resulted in significant increase of p53 levels, reaching almost 2-fold in hepatocellular carcinoma cells. In parallel to experimental screening, two representative and orthogonal in silico screening methodologies were implemented for enabling the retrospective assessment of virtual screening performance on a case-specific basis. Results showed that both techniques performed at an acceptable and fairly comparable level, with a slight advantage of the structure-based over the ligand-based approach. However, both approaches demonstrated notable sensitivity upon parameters such as screening template choice and treatment of redundancy in the enumerated compound collection. An effort to combine insight derived by sequential implementation of the two methods afforded poor further improvement of screening performance. Overall, the presented assessment highlights the relation between improper use of enrichment metrics and misleading results, and demonstrates the inherent delicacy of in silico methods, emphasizing the challenging character of virtual screening protocol optimization. View Full-Text
Keywords: casein kinase-1; NCI diversity set-II; structure-based screening; ligand-based screening; Glide; ROCS; enrichment calculation; p53 levels; compound collection enumeration; screening template casein kinase-1; NCI diversity set-II; structure-based screening; ligand-based screening; Glide; ROCS; enrichment calculation; p53 levels; compound collection enumeration; screening template
Figures

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Myrianthopoulos, V.; Lozach, O.; Zareifi, D.; Alexopoulos, L.; Meijer, L.; Gorgoulis, V.G.; Mikros, E. Combined Virtual and Experimental Screening for CK1 Inhibitors Identifies a Modulator of p53 and Reveals Important Aspects of in Silico Screening Performance. Int. J. Mol. Sci. 2017, 18, 2102.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top