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Pharmacophore-based screening and drug repurposing exemplified on glycogen synthase kinase-3 inhibitors

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Abstract

The current study was conducted to elaborate a novel pharmacophore model to accurately map selective glycogen synthase kinase-3 (GSK-3) inhibitors, and perform virtual screening and drug repurposing. Pharmacophore modeling was developed using PHASE on a data set of 203 maleimides. Two benchmarking validation data sets with focus on selectivity were assembled using ChEMBL and PubChem GSK-3 confirmatory assays. A drug repurposing experiment linking pharmacophore matching with drug information originating from multiple data sources was performed. A five-point pharmacophore model was built consisting of a hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H), and two rings (RR). An atom-based 3D quantitative structure–activity relationship (QSAR) model showed good correlative and satisfactory predictive abilities (training set \({R}^{2}= 0.904\); test set: \({Q}^{2}= 0.676\); whole data set: stability \(s = 0.803\)). Virtual screening experiments revealed that selective GSK-3 inhibitors are ranked preferentially by Hypo-1, but fail to retrieve nonselective compounds. The pharmacophore and 3D QSAR models can provide assistance to design novel, potential GSK-3 inhibitors with high potency and selectivity pattern, with potential application for the treatment of GSK-3-driven diseases. A class of purine nucleoside antileukemic drugs was identified as potential inhibitor of GSK-3, suggesting the reassessment of the target range of these drugs.

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Abbreviations

GSK-3:

Glycogen synthase kinase-3

CMGC:

Kinase group named after the initials of some members, which include key kinases: the MAPK growth and stress response kinases, the cell cycle CDK (cyclin-dependent kinases), and kinases involved in splicing and metabolic control

CDK-2:

Cyclin-dependent kinase-2

DISCO:

DIStance COmparison (DISCO) technique

DUD:

Directory of useful decoys

MUV:

Maximum unbiased validation

HTS:

High-throughput screening

NCI:

National Cancer Institute

CDK-4:

Cyclin-dependent kinase-4

PKC:

Protein kinase C

RMSD:

Root mean squared deviation

PDB:

Protein Data Bank

FDA:

Food and Drug Administration

ROC:

Receiver operating characteristic

AUC:

Area under the curve

AROCE:

Addition of ROC enrichment

eROCE:

Exponential ROC enrichment

OPLS:

Optimized potentials for liquid simulations

PLS:

Partial least squares

CoMFA:

Comparative molecular field analysis

NF-kappaB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

XIAP:

X-linked inhibitor of apoptosis protein

MLL:

Myeloid/lymphoid or mixed-lineage leukemia

CLL:

Chronic lymphocytic leukemia

MM:

Multiple myeloma

AML:

Acute myeloid leukemia

CML:

Chronic myelogenous leukemia

T-ALL:

T-cell acute lymphoblastic leukemia

T-LBL:

T-cell acute lymphoblastic lymphoma

PI3K:

Phosphatidylinositol-4,5-bisphosphate 3-kinase

Akt:

Serine/threonine kinase Akt (also known as protein kinase B or PKB)

mTOR:

Mechanistic target of rapamycin, also known as mammalian target of rapamycin (mTOR)

FOXO:

Forkhead box O3

Cn:

Calcineurin

Bcl-2:

B-cell lymphoma 2

MCL-1:

Induced myeloid leukemia cell differentiation protein Mcl-1

B-CLL:

B-cell chronic lymphocytic leukemia

p53:

Tumor protein p53

HCL:

Hairy cell leukemia

Wnt:

Wnt signaling pathway

Mdm2:

Mouse double minute 2 homolog

VEGFR:

Vascular endothelial growth factor receptor

5-HT3:

5-Hydroxytryptamine receptor

IBS:

Irritable bowel syndrome

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Acknowledgements

We thank Chemaxon Ltd., OpenEye Ltd., and Accelrys Inc. for providing academic license. This project was financially supported by the Project No. 1.2/2016 of the Institute of Chemistry of Romanian Academy, Timisoara.

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  1. Department of Computational Chemistry, The Institute of Chemistry Timisoara of Romanian Academy, 24 Mihai Viteazul Avenue, 300223, Timisoara, Romania

    Luminita Crisan, Sorin Avram & Liliana Pacureanu

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  1. Luminita Crisan
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Dedicated to the 150th anniversary of the Romanian Academy.

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Crisan, L., Avram, S. & Pacureanu, L. Pharmacophore-based screening and drug repurposing exemplified on glycogen synthase kinase-3 inhibitors. Mol Divers 21, 385–405 (2017). https://doi.org/10.1007/s11030-016-9724-5

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