Discovery of novel Flt3 inhibitory chemotypes through extensive ligand-based and new structure-based pharmacophore modelling methods

Reem Fawaz Abutayeh; Mutasem O Taha

doi:10.1016/j.jmgm.2019.01.011

Discovery of novel Flt3 inhibitory chemotypes through extensive ligand-based and new structure-based pharmacophore modelling methods

J Mol Graph Model. 2019 May:88:128-151. doi: 10.1016/j.jmgm.2019.01.011. Epub 2019 Jan 22.

Authors

Reem Fawaz Abutayeh¹, Mutasem O Taha²

Affiliations

¹ Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science Private University, Amman, Jordan.
² Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman, Jordan. Electronic address: mutasem@ju.edu.jo.

PMID: 30703688
DOI: 10.1016/j.jmgm.2019.01.011

Abstract

Flt3 is an oncogenic kinase involved in different types of leukemia. It is most prominently associated with acute myeloid leukemia (AML). Flt3-specific inhibitors have shown promising results in interfering with AML prompting us to model this interesting target. We implemented ligand-based, QSAR-guided, pharmacophore exploration combined with novel structure-based computational workflow based on docking-based comparative intermolecular contacts analysis (db-CICA) combined with homology modelling to explore the pharmacophoric features of 93 diverse cyclic Flt3 inhibitors. The resulting pharmacophore models were used as virtual search queries to scan the National Cancer Institute (NCI) database for novel Flt3 inhibitory leads. Ten hits of novel scaffolds were captured showing anti-Flt3 IC₅₀ values ranging from 1.2 to 14.7 μM. Interestingly, six of them illustrated low micromolar and submicromolar potencies against the mutated active form of Flt3 (Flt3D835Y) and the related vascular endothelial growth factor receptor 2 (VEGFR2).

Keywords: Flt3; Homology modelling; In vitro assay; MLR; Pharmacophore; QSAR; db-CICA; kNN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Drug Discovery* / methods
Humans
Kinetics
Ligands
Molecular Conformation
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Protein Binding
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Quantitative Structure-Activity Relationship*
ROC Curve
Reproducibility of Results
Software
Workflow
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
fms-Like Tyrosine Kinase 3 / chemistry*

Substances

Ligands
Protein Kinase Inhibitors
FLT3 protein, human
fms-Like Tyrosine Kinase 3