Discovery of novel Flt3 inhibitory chemotypes through extensive ligand-based and new structure-based pharmacophore modelling methods.
J Mol Graph Model
; 88: 128-151, 2019 05.
Article
in En
| MEDLINE
| ID: mdl-30703688
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⯵M. 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).
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Quantitative Structure-Activity Relationship
/
Protein Kinase Inhibitors
/
Fms-Like Tyrosine Kinase 3
/
Drug Discovery
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
J Mol Graph Model
Journal subject:
BIOLOGIA MOLECULAR
Year:
2019
Document type:
Article
Affiliation country:
Jordan
Country of publication:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
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US
/
USA