Structure-activity Relationship Study on Therapeutically Relevant EGFR Double Mutant Inhibitors.
EGFR
amino-pyrimidine
descriptors
double mutant inhibitor
fragment based QSAR
interaction descriptors
reversible inhibitors.
Journal
Medicinal chemistry (Shariqah (United Arab Emirates))
ISSN: 1875-6638
Titre abrégé: Med Chem
Pays: Netherlands
ID NLM: 101240303
Informations de publication
Date de publication:
2020
2020
Historique:
received:
31
08
2018
revised:
14
12
2018
accepted:
18
12
2018
pubmed:
8
2
2019
medline:
18
2
2020
entrez:
8
2
2019
Statut:
ppublish
Résumé
EGFR is a clinically approved drug target in cancer. The first generation tyrosine kinase inhibitors targeting L858R mutated EGFR are routinely used to treat non-small cell lung cancer (NSCLC). However, the presence of a secondary mutation (T790M) tenders these inhibitors ineffective and thus results in the relapse of the disease. New reversible inhibitors are required, which act against T790M/L858R (TMLR) double mutants and overcome resistance. In the present study, various Fragment based QSAR (G-QSAR) models along with interaction terms have been studied for amino-pyrimidine derivatives having biological activity against TMLR mutant enzyme. The G-QSAR models developed using partial least squares regression via stepwise forward- backward variable selection technique showed the best results. The model showed a high correlation coefficient (r² = 0.86), cross-validation coefficient (q² = 0.81) and predicted correlation (predicted r² = 0.62), which indicated that the model is robust and predictive. Based on the model, it was revealed that at R1 position increasing saturated carbon (number of -CH atom connected with 3 single bonds i.e. SsssCHcount) and retention index (chi3) is desired for the enhancement of bioactivity. Additionally, at the R2 position, increasing lipophilic character (slogp) and at site R3, the polarizability of compound need to be increased for better inhibitory activity. We further studied the contribution of interactions among significant descriptors in enhancing the activity of the compounds. It revealed that the presence of Sum((R1-SsssCHcount, R2-slogp) and Mult(R1-chi3, R3-polarizabilityAHC) are the most significantly influencing descriptors. We further compared the variation in the most and least active compounds which established that retention of the above properties is essential for imparting significant inhibitory activity to these molecules. The study provides site specific information wherein chemical group variation influences the inhibitory potency of TMLR amino-pyrimidine inhibitors, which can be used for designing new molecules with the desired activity.
Sections du résumé
BACKGROUND
BACKGROUND
EGFR is a clinically approved drug target in cancer. The first generation tyrosine kinase inhibitors targeting L858R mutated EGFR are routinely used to treat non-small cell lung cancer (NSCLC). However, the presence of a secondary mutation (T790M) tenders these inhibitors ineffective and thus results in the relapse of the disease.
OBJECTIVE
OBJECTIVE
New reversible inhibitors are required, which act against T790M/L858R (TMLR) double mutants and overcome resistance.
METHOD
METHODS
In the present study, various Fragment based QSAR (G-QSAR) models along with interaction terms have been studied for amino-pyrimidine derivatives having biological activity against TMLR mutant enzyme.
RESULTS
RESULTS
The G-QSAR models developed using partial least squares regression via stepwise forward- backward variable selection technique showed the best results. The model showed a high correlation coefficient (r² = 0.86), cross-validation coefficient (q² = 0.81) and predicted correlation (predicted r² = 0.62), which indicated that the model is robust and predictive. Based on the model, it was revealed that at R1 position increasing saturated carbon (number of -CH atom connected with 3 single bonds i.e. SsssCHcount) and retention index (chi3) is desired for the enhancement of bioactivity. Additionally, at the R2 position, increasing lipophilic character (slogp) and at site R3, the polarizability of compound need to be increased for better inhibitory activity. We further studied the contribution of interactions among significant descriptors in enhancing the activity of the compounds. It revealed that the presence of Sum((R1-SsssCHcount, R2-slogp) and Mult(R1-chi3, R3-polarizabilityAHC) are the most significantly influencing descriptors. We further compared the variation in the most and least active compounds which established that retention of the above properties is essential for imparting significant inhibitory activity to these molecules.
CONCLUSION
CONCLUSIONS
The study provides site specific information wherein chemical group variation influences the inhibitory potency of TMLR amino-pyrimidine inhibitors, which can be used for designing new molecules with the desired activity.
Identifiants
pubmed: 30727906
pii: MC-EPUB-96443
doi: 10.2174/1573406415666190206204853
doi:
Substances chimiques
Amines
0
Protein Kinase Inhibitors
0
Pyrimidines
0
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
pyrimidine
K8CXK5Q32L
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
52-62Informations de copyright
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