Computational identification of 2,4-disubstituted amino-pyrimidines as L858R/T790M-EGFR double mutant inhibitors using pharmacophore mapping, molecular docking, binding free energy calculation, DFT study and molecular dynamic simulation.

Autor: Pawara R; Division of Computer-Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, District Dhule, Shirpur, Maharashtra 425 405 India., Ahmad I; Division of Computer-Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, District Dhule, Shirpur, Maharashtra 425 405 India., Surana S; Division of Computer-Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, District Dhule, Shirpur, Maharashtra 425 405 India., Patel H; Division of Computer-Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, District Dhule, Shirpur, Maharashtra 425 405 India.
Jazyk: angličtina
Zdroj: In silico pharmacology [In Silico Pharmacol] 2021 Oct 06; Vol. 9 (1), pp. 54. Date of Electronic Publication: 2021 Oct 06 (Print Publication: 2021).
DOI: 10.1007/s40203-021-00113-x
Abstrakt: Pharmacophore modelling studies have been performed for a series of 2,4-disubstituted-pyrimidines derivatives as EGFR L858R/T790M tyrosine kinase inhibitors. The high scoring AARR.15 hypothesis was selected as the best pharmacophore model with the highest survival score of 3.436 having two hydrogen bond acceptors and two aromatic ring features. Pharmacophore-based virtual screening followed by structure-based yielded the six molecules (ZINC17013227, ZINC17013215, ZINC9573324, ZINC9573445, ZINC24023331 and ZINC17013503) from the ZINC database with significant in silico predicted activity and strong binding affinity towords the EGFR L858R/T790M tyrosine kinase. In silico toxicity and cytochrome profiling indicates that all the 06 virtually screened compounds were substrate/inhibitors of the CYP-3A4 metabolizing enzyme and were non-carcinogenic and devoid of Ames mutagenesis. Density functional theory (DFT) and molecular dynamic (MD) simulation further validated the obtained hits.
Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-021-00113-x.
Competing Interests: Conflict of interestAll authors declare no actual or potential conflict of interest including any financial, personal, or other relationships with other people or organizations.
(© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.)
Databáze: MEDLINE
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