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Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors.
J Mol Model. 2009 Dec; 15(12):1463-79.JM

Abstract

Molecular modeling and docking studies along with three-dimensional quantitative structure relationships (3D-QSAR) studies have been used to determine the correct binding mode of glycogen synthase kinase 3beta (GSK-3beta) inhibitors. The approaches of comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) are used for the 3D-QSAR of 51 substituted benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors. Two binding modes of the inhibitors to the binding site of GSK-3beta are investigated. The binding mode 1 yielded better 3D-QSAR correlations using both CoMFA and CoMSIA methodologies. The three-component CoMFA model from the steric and electrostatic fields for the experimentally determined pIC(50) values has the following statistics: R(2)(cv) = 0.386 nd SE(cv) = 0.854 for the cross-validation, and R(2) = 0.811 and SE = 0.474 for the fitted correlation. F (3,47) = 67.034, and probability of R(2) = 0 (3,47) = 0.000. The binding mode suggested by the results of this study is consistent with the preliminary results of X-ray crystal structures of inhibitor-bound GSK-3beta. The 3D-QSAR models were used for the estimation of the inhibitory potency of two additional compounds.

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Authors+Show Affiliations

Kim KH
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 60612, USA. pkhkim@gmail.com
Gaisina I
No affiliation info available
Gallier F
No affiliation info available
Holzle D
No affiliation info available
Blond SY
No affiliation info available
Mesecar A
No affiliation info available
Kozikowski AP
No affiliation info available

MeSH

Glycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaLisinoprilMaleimidesModels, MolecularQuantitative Structure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19440740

Citation

Kim, Ki Hwan, et al. "Use of Molecular Modeling, Docking, and 3D-QSAR Studies for the Determination of the Binding Mode of Benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta Inhibitors." Journal of Molecular Modeling, vol. 15, no. 12, 2009, pp. 1463-79.
Kim KH, Gaisina I, Gallier F, et al. Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors. J Mol Model. 2009;15(12):1463-79.
Kim, K. H., Gaisina, I., Gallier, F., Holzle, D., Blond, S. Y., Mesecar, A., & Kozikowski, A. P. (2009). Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors. Journal of Molecular Modeling, 15(12), 1463-79. https://doi.org/10.1007/s00894-009-0498-x
Kim KH, et al. Use of Molecular Modeling, Docking, and 3D-QSAR Studies for the Determination of the Binding Mode of Benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta Inhibitors. J Mol Model. 2009;15(12):1463-79. PubMed PMID: 19440740.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors. AU - Kim,Ki Hwan, AU - Gaisina,Irina, AU - Gallier,Franck, AU - Holzle,Denise, AU - Blond,Sylvie Y, AU - Mesecar,Andrew, AU - Kozikowski,Alan P, Y1 - 2009/05/14/ PY - 2008/10/30/received PY - 2009/04/16/accepted PY - 2009/5/15/entrez PY - 2009/5/15/pubmed PY - 2010/3/10/medline SP - 1463 EP - 79 JF - Journal of molecular modeling JO - J Mol Model VL - 15 IS - 12 N2 - Molecular modeling and docking studies along with three-dimensional quantitative structure relationships (3D-QSAR) studies have been used to determine the correct binding mode of glycogen synthase kinase 3beta (GSK-3beta) inhibitors. The approaches of comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) are used for the 3D-QSAR of 51 substituted benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors. Two binding modes of the inhibitors to the binding site of GSK-3beta are investigated. The binding mode 1 yielded better 3D-QSAR correlations using both CoMFA and CoMSIA methodologies. The three-component CoMFA model from the steric and electrostatic fields for the experimentally determined pIC(50) values has the following statistics: R(2)(cv) = 0.386 nd SE(cv) = 0.854 for the cross-validation, and R(2) = 0.811 and SE = 0.474 for the fitted correlation. F (3,47) = 67.034, and probability of R(2) = 0 (3,47) = 0.000. The binding mode suggested by the results of this study is consistent with the preliminary results of X-ray crystal structures of inhibitor-bound GSK-3beta. The 3D-QSAR models were used for the estimation of the inhibitory potency of two additional compounds. SN - 0948-5023 UR - https://www.unboundmedicine.com/medline/citation/19440740/Use_of_molecular_modeling_docking_and_3D_QSAR_studies_for_the_determination_of_the_binding_mode_of_benzofuran_3_yl__indol_3_yl_maleimides_as_GSK_3beta_inhibitors_ L2 - https://dx.doi.org/10.1007/s00894-009-0498-x DB - PRIME DP - Unbound Medicine ER -
Grapherence [↓2 ↑46]

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