Format

Send to

Choose Destination
Int J Mol Sci. 2017 Oct 6;18(10). pii: E2102. 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.

Author information

1
Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens, Greece. vmyriant@pharm.uoa.gr.
2
Protein Phosphorylation & Human Disease Group, Station Biologique, B. P. 74, CEDEX 29682 Roscoff, Bretagne, France. olivier.lozach@univ-brest.fr.
3
ProtATonce Ltd., 15343 Athens, Greece. danae.zar@gmail.com.
4
School of Mechanical Engineering, National Technical University of Athens, 15780 Athens, Greece. leo@mail.ntua.gr.
5
ManRos Therapeutics, Perharidy Research Center, Roscoff, 29680 Bretagne, France. meijer@manros-therapeutics.com.
6
Department of Histology-Embryology, School of Medicine, University of Athens, Mikras Asias 75, GR-11527 Athens, Greece. vgorg@med.uoa.gr.
7
Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece. vgorg@med.uoa.gr.
8
Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, M13 9NT Manchester, UK. vgorg@med.uoa.gr.
9
Department of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens, Greece. mikros@pharm.uoa.gr.
10
"Athena" Research and Innovation Center, 15125 Athens, Greece. mikros@pharm.uoa.gr.

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.

KEYWORDS:

Glide; NCI diversity set-II; ROCS; casein kinase-1; compound collection enumeration; enrichment calculation; ligand-based screening; p53 levels; screening template; structure-based screening

PMID:
28984824
PMCID:
PMC5666784
DOI:
10.3390/ijms18102102
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center