Elaboration of Novel TTK1 Inhibitory Leads via QSAR-Guided Selection of Crystallographic Pharmacophores Followed By In Vitro Assay.
Curr Comput Aided Drug Des
; 17(4): 511-522, 2021.
Article
in En
| MEDLINE
| ID: mdl-32525782
ABSTRACT
INTRODUCTION:
Tyrosine threonine kinase (TTK1) is a key regulator of chromosome segregation. Recently, TTK targeting came into focus for the enhancement of possible anticancer therapies.OBJECTIVE:
In this regard, we employed our well-known method of QSAR-guided selection of the best crystallographic pharmacophore(s) to discover considerable binding interactions that transfer inhibitors into TTK1 binding site.METHODS:
Sixty-one TTK1 crystallographic complexes were used to extract 315 pharmacophore hypotheses. QSAR modeling was subsequently used to choose a single crystallographic pharmacophore that, when combined with other physicochemical descriptors, elucidates discrepancy in bioactivity of 55 miscellaneous inhibitors.RESULTS:
The best QSAR model was robust and predictive (r2(55) = 0.75, r2LOO = 0.72 , r2press against external testing list of 12 compounds = 0.67), Standard error of estimate (training set) (S)= 0.63 , Standard error of estimate (testing set)(Stest) = 0.62. The resulting pharmacophore and QSAR models were used to scan the National Cancer Institute (NCI) database for new TTK1 inhibitors.CONCLUSION:
Five hits confirmed significant TTK1 inhibitory profiles with IC50 values ranging between 11.7 and 76.6 mM.Key words
Full text:
1
Database:
MEDLINE
Main subject:
Protein-Tyrosine Kinases
/
Quantitative Structure-Activity Relationship
Type of study:
Prognostic_studies
Language:
En
Year:
2021
Type:
Article