Combined pharmacophore modeling, docking, and 3D-QSAR studies of PLK1 inhibitors

Abstract

Polo-like kinase 1, an important enzyme with diverse biological actions in cell mitosis, is a promising target for developing novel anticancer drugs. A combined molecular docking, structure-based pharmacophore modeling and three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a set of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. The common substructure, molecular docking and pharmacophore-based alignment were used to develop different 3D-QSAR models. The comparative molecular field analysis (CoMFA) and comparative molecule similarity indices analysis (CoMSIA) models gave statistically significant results. These models showed good q(2) and r(2) (pred) values and revealed a good response to test set validation. All of the structural insights obtained from the 3D-QSAR contour maps are consistent with the available crystal structure of PLK1. The contour maps obtained from the 3D-QSAR models in combination with the structure based pharmacophore model help to better interpret the structure-activity relationship. These satisfactory results may aid the design of novel PLK1 inhibitors. This is the first report on 3D-QSAR study of PLK1 inhibitors.

Keywords: 3D-QSAR; PLK1; molecular docking; pharmacophore.

Figure 1

The co-crystal binding mode of compound 73 with PLK1. The hydrogen bond is represented with red dotted line.

Figure 2

The common substructure based alignment.

Figure 3

The resultant conformations from GLIDE docking.

Figure 4

(a) Pharmacophore model derived from 2YAC; (b) Pharmacophore model derived from 3KB7; (c) The merged model; (d) The compounds alignment based on the merged model. Features are color-coded with magenta for hydrogen-bond donor, green for hydrogen-bond acceptor, light-blue for hydrophobic, red for ionizable positive.

Figure 5

Plot of predicted vs. experimental values of (a) CoMFA model 2 and (b) CoMSIA models 4, 5 and 6.

Figure 6

The CoMFA contour map of model 2 combined with compound 73. (a) Steric field distribution on the background of protein surface; and (b) electrostatic field distribution on the background of electrostatic potential surface colored from purple to red owing to the increase of electron density. Green contours indicate regions where bulky groups increase activity, whereas yellow contours indicate regions where bulky groups decrease activity. Red contours suggest negative charge favoring activity, whereas blue contours suggest positive charge favoring activity.

Figure 7

The CoMSIA contour map combined with compound 73. Steric field distribution for (a) model 4, (b) model 5 and (c) model 6, on the background of protein surface. Electrostatic field distribution for (d) model 4, (e) model 5, and (f) model 6, on the background of electrostatic potential surface colored from purple to red owing to the increase of electron density. Hydrogen bond donor field distribution for (g) model 4, (h) model 5 and (i) model 6. Green contours indicate regions where bulky groups increase activity, whereas yellow contours indicate regions where bulky groups decrease activity. Positive potential favored areas are in blue, and positive potential unfavored areas are in red. Cyan and purple contours indicate favorable and unfavorable hydrogen bond donor group. The hydrogen bond is represented with orange dotted line.

Figure 7

The CoMSIA contour map combined with compound 73. Steric field distribution for (a) model 4, (b) model 5 and (c) model 6, on the background of protein surface. Electrostatic field distribution for (d) model 4, (e) model 5, and (f) model 6, on the background of electrostatic potential surface colored from purple to red owing to the increase of electron density. Hydrogen bond donor field distribution for (g) model 4, (h) model 5 and (i) model 6. Green contours indicate regions where bulky groups increase activity, whereas yellow contours indicate regions where bulky groups decrease activity. Positive potential favored areas are in blue, and positive potential unfavored areas are in red. Cyan and purple contours indicate favorable and unfavorable hydrogen bond donor group. The hydrogen bond is represented with orange dotted line.

Figure 8

The pharmacophore model superimposed with (a) steric; (b) electrostatic and (c) hydrogen bond donor and acceptor contours of model 6. The pharmacophore features are colored the same as in Figure 4. The contours are depicted as mesh.

Figure 9

Schematic representation for the SAR of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. R¹: medium-sized substituent with hydrogen bond donor and acceptor; R²: open-chain alkyl group with less than three carbon atoms or unsubstituted hydrogen; R³: hydrophobic group with small size and strong electron-withdrawing atom, especially hydrogen bond acceptor; R⁴: bulky substituents simultaneously with hydrophobic and hydrophilic moiety.

Figure 10

Distribution of activities (pIC50) for the training set and the test set versus numbers of compounds. The training set and the test set are colored as red and blue, respectively.

Figure 11

The most common substructure used in common substructure-based alignment.