Molecular Modeling Studies of <i>N</i>-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3

Overexpression and frequent mutations in FMS-like tyrosine kinase-3 (FLT3) are considered risk factors for severe acute myeloid leukemia (AML). Hyperactive FLT3 induces premature activation of multiple intracellular signaling pathways, resulting in cell proliferation and anti-apoptosis. We conducted...

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Autores principales:	Suparna Ghosh, Seketoulie Keretsu, Seung Joo Cho
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	FMS-like tyrosine kinase-3 acute myeloid leukemia MD simulation binding free energy 3D-QSAR CoMFA Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/0cfe605055e74e88b055e8686b248eeb
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spelling	oai:doaj.org-article:0cfe605055e74e88b055e8686b248eeb2021-11-25T17:57:23ZMolecular Modeling Studies of <i>N</i>-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-310.3390/ijms2222125111422-00671661-6596https://doaj.org/article/0cfe605055e74e88b055e8686b248eeb2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12511https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Overexpression and frequent mutations in FMS-like tyrosine kinase-3 (FLT3) are considered risk factors for severe acute myeloid leukemia (AML). Hyperactive FLT3 induces premature activation of multiple intracellular signaling pathways, resulting in cell proliferation and anti-apoptosis. We conducted the computational modeling studies of 40 pyrimidine-4,6-diamine-based compounds by integrating docking, molecular dynamics, and three-dimensional structure–activity relationship (3D-QSAR). Molecular docking showed that K644, C694, F691, E692, N701, D829, and F830 are critical residues for the binding of ligands at the hydrophobic active site. Molecular dynamics (MD), together with Molecular Mechanics Poison–Boltzmann/Generalized Born Surface Area, i.e., MM-PB(GB)SA, and linear interaction energy (LIE) estimation, provided critical information on the stability and binding affinity of the selected docked compounds. The MD study suggested that the mutation in the gatekeeper residue F691 exhibited a lower binding affinity to the ligand. Although, the mutation in D835 in the activation loop did not exhibit any significant change in the binding energy to the most active compound. We developed the ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models. CoMFA (<i>q</i><sup>2</sup> = 0.802, <i>r</i><sup>2</sup> = 0.983, and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mi>Q</mi><mrow><mi>F</mi><mn>3</mn></mrow><mn>2</mn></msubsup></mrow></semantics></math></inline-formula> = 0.698) and CoMSIA (<i>q</i><sup>2</sup> = 0.725, <i>r</i><sup>2</sup> = 0.965 and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mi>Q</mi><mrow><mi>F</mi><mn>3</mn></mrow><mn>2</mn></msubsup></mrow></semantics></math></inline-formula> = 0.668) established the structure–activity relationship (SAR) and showed a reasonable external predictive power. The contour maps from the CoMFA and CoMSIA models could explain valuable information about the favorable and unfavorable positions for chemical group substitution, which can increase or decrease the inhibitory activity of the compounds. In addition, we designed 30 novel compounds, and their predicted pIC<sub>50</sub> values were assessed with the CoMSIA model, followed by the assessment of their physicochemical properties, bioavailability, and free energy calculation. The overall outcome could provide valuable information for designing and synthesizing more potent FLT3 inhibitors.Suparna GhoshSeketoulie KeretsuSeung Joo ChoMDPI AGarticleFMS-like tyrosine kinase-3acute myeloid leukemiaMD simulationbinding free energy3D-QSARCoMFABiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12511, p 12511 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	FMS-like tyrosine kinase-3 acute myeloid leukemia MD simulation binding free energy 3D-QSAR CoMFA Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	FMS-like tyrosine kinase-3 acute myeloid leukemia MD simulation binding free energy 3D-QSAR CoMFA Biology (General) QH301-705.5 Chemistry QD1-999 Suparna Ghosh Seketoulie Keretsu Seung Joo Cho Molecular Modeling Studies of <i>N</i>-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3
description	Overexpression and frequent mutations in FMS-like tyrosine kinase-3 (FLT3) are considered risk factors for severe acute myeloid leukemia (AML). Hyperactive FLT3 induces premature activation of multiple intracellular signaling pathways, resulting in cell proliferation and anti-apoptosis. We conducted the computational modeling studies of 40 pyrimidine-4,6-diamine-based compounds by integrating docking, molecular dynamics, and three-dimensional structure–activity relationship (3D-QSAR). Molecular docking showed that K644, C694, F691, E692, N701, D829, and F830 are critical residues for the binding of ligands at the hydrophobic active site. Molecular dynamics (MD), together with Molecular Mechanics Poison–Boltzmann/Generalized Born Surface Area, i.e., MM-PB(GB)SA, and linear interaction energy (LIE) estimation, provided critical information on the stability and binding affinity of the selected docked compounds. The MD study suggested that the mutation in the gatekeeper residue F691 exhibited a lower binding affinity to the ligand. Although, the mutation in D835 in the activation loop did not exhibit any significant change in the binding energy to the most active compound. We developed the ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models. CoMFA (<i>q</i><sup>2</sup> = 0.802, <i>r</i><sup>2</sup> = 0.983, and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mi>Q</mi><mrow><mi>F</mi><mn>3</mn></mrow><mn>2</mn></msubsup></mrow></semantics></math></inline-formula> = 0.698) and CoMSIA (<i>q</i><sup>2</sup> = 0.725, <i>r</i><sup>2</sup> = 0.965 and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mi>Q</mi><mrow><mi>F</mi><mn>3</mn></mrow><mn>2</mn></msubsup></mrow></semantics></math></inline-formula> = 0.668) established the structure–activity relationship (SAR) and showed a reasonable external predictive power. The contour maps from the CoMFA and CoMSIA models could explain valuable information about the favorable and unfavorable positions for chemical group substitution, which can increase or decrease the inhibitory activity of the compounds. In addition, we designed 30 novel compounds, and their predicted pIC<sub>50</sub> values were assessed with the CoMSIA model, followed by the assessment of their physicochemical properties, bioavailability, and free energy calculation. The overall outcome could provide valuable information for designing and synthesizing more potent FLT3 inhibitors.
format	article
author	Suparna Ghosh Seketoulie Keretsu Seung Joo Cho
author_facet	Suparna Ghosh Seketoulie Keretsu Seung Joo Cho
author_sort	Suparna Ghosh
title	Molecular Modeling Studies of <i>N</i>-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3
title_short	Molecular Modeling Studies of <i>N</i>-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3
title_full	Molecular Modeling Studies of <i>N</i>-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3
title_fullStr	Molecular Modeling Studies of <i>N</i>-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3
title_full_unstemmed	Molecular Modeling Studies of <i>N</i>-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3
title_sort	molecular modeling studies of <i>n</i>-phenylpyrimidine-4-amine derivatives for inhibiting fms-like tyrosine kinase-3
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0cfe605055e74e88b055e8686b248eeb
work_keys_str_mv	AT suparnaghosh molecularmodelingstudiesofiniphenylpyrimidine4aminederivativesforinhibitingfmsliketyrosinekinase3 AT seketouliekeretsu molecularmodelingstudiesofiniphenylpyrimidine4aminederivativesforinhibitingfmsliketyrosinekinase3 AT seungjoocho molecularmodelingstudiesofiniphenylpyrimidine4aminederivativesforinhibitingfmsliketyrosinekinase3
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Molecular Modeling Studies of <i>N</i>-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3

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