TY - JOUR
T1 - Comparative molecular field analysis of flavonoid inhibitors of the PIM-1 kinase
AU - Holder, Sheldon
AU - Lilly, Michael
AU - Brown, Milton L.
N1 - Funding Information:
We thank Ryan Bremer and Plexxikon, Inc. for making the co-crystal structures of PIM-1 bound to quercetagetin and myricetin available to us in advance of publication for use in this study. We thank the Drug Discovery Program at Georgetown Medical Center for financial support.
PY - 2007/10/1
Y1 - 2007/10/1
N2 - The PIM-1 protein, the product of the pim-1 oncogene, is a serine/threonine kinase. Dysregulation of the PIM-1 kinase has been implicated in the development of human malignancies including lymphomas, leukemias, and prostate cancer. Comparative molecular field analysis (CoMFA) is a 3-D QSAR technique that has been widely used, with notable success, to correlate biological activity with the steric and electrostatic properties of ligands. We have used a set of 15 flavonoid inhibitors of the PIM-1 kinase, aligned de novo by common substructure, to generate a CoMFA model for the purpose of elucidating the steric and electrostatic properties involved in flavonoid binding to the PIM-1 kinase. Partial least squares correlation between observed and predicted inhibitor potency (expressed as -log IC50), using a non-cross-validated partial least squares analysis, generated a non-cross-validated q2 = 0.805 for the training set (n = 15) of flavonoids. The CoMFA generated steric map indicated that the PIM-1-binding site was sterically hindered, leading to more efficient binding of planar molecules over (R) or (S) compounds. The electrostatic map identified that positive charges near the flavonoid atom C8 and negative charges near C4′ increased flavonoid binding. The CoMFA model accurately predicted the potency of a test set of flavonoids (n = 6), generating a correlation between observed and predicted potency of q2 = 0.825. CoMFA models generated from additional alignment rules, which were guided by co-crystal structure ligand orientations, did not improve the correlative value of the model. Superimposing the PIM-1 kinase crystal structure onto the CoMFA contours validated the steric and electrostatic maps, elucidating the amino acid residues that potentially contribute to the CoMFA fields. Thus we have generated the first predictive model that may be used for the rational design of small-molecule inhibitors of the PIM-1 kinase.
AB - The PIM-1 protein, the product of the pim-1 oncogene, is a serine/threonine kinase. Dysregulation of the PIM-1 kinase has been implicated in the development of human malignancies including lymphomas, leukemias, and prostate cancer. Comparative molecular field analysis (CoMFA) is a 3-D QSAR technique that has been widely used, with notable success, to correlate biological activity with the steric and electrostatic properties of ligands. We have used a set of 15 flavonoid inhibitors of the PIM-1 kinase, aligned de novo by common substructure, to generate a CoMFA model for the purpose of elucidating the steric and electrostatic properties involved in flavonoid binding to the PIM-1 kinase. Partial least squares correlation between observed and predicted inhibitor potency (expressed as -log IC50), using a non-cross-validated partial least squares analysis, generated a non-cross-validated q2 = 0.805 for the training set (n = 15) of flavonoids. The CoMFA generated steric map indicated that the PIM-1-binding site was sterically hindered, leading to more efficient binding of planar molecules over (R) or (S) compounds. The electrostatic map identified that positive charges near the flavonoid atom C8 and negative charges near C4′ increased flavonoid binding. The CoMFA model accurately predicted the potency of a test set of flavonoids (n = 6), generating a correlation between observed and predicted potency of q2 = 0.825. CoMFA models generated from additional alignment rules, which were guided by co-crystal structure ligand orientations, did not improve the correlative value of the model. Superimposing the PIM-1 kinase crystal structure onto the CoMFA contours validated the steric and electrostatic maps, elucidating the amino acid residues that potentially contribute to the CoMFA fields. Thus we have generated the first predictive model that may be used for the rational design of small-molecule inhibitors of the PIM-1 kinase.
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U2 - 10.1016/j.bmc.2007.06.025
DO - 10.1016/j.bmc.2007.06.025
M3 - Article
C2 - 17637507
AN - SCOPUS:34547689097
SN - 0968-0896
VL - 15
SP - 6463
EP - 6473
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 19
ER -