3D-QSAR and molecular docking studies on fused pyrazoles as p38α mitogen-activated protein kinase inhibitors

Abstract

The p38α mitogen-activated protein kinase (MAPK) has become an attractive target for the treatment of many diseases such as rheumatoid arthritis, inflammatory bowel disease and Crohn's disease. In this paper, 3D-QSAR and molecular docking studies were performed on 59 p38α MAPK inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to determine the structural requirements for potency in inhibiting p38α MAPK. The resulting model of CoMFA and CoMSIA exhibited good r(2) (cv) values of 0.725 and 0.609, and r(2) values of 0.961 and 0.905, respectively. Molecular docking was used to explore the binding mode between the inhibitors and p38α MAPK. We have accordingly designed a series of novel p38α MAPK inhibitors by utilizing the structure-activity relationship (SAR) results revealed in the present study, which were predicted with excellent potencies in the developed models. The results provided a useful guide to design new compounds for p38α MAPK inhibitors.

Keywords: 3D-QSAR; CoMFA; CoMSIA; docking; p38α mitogen-activated protein kinase.

Figure 1

Fragment used as a common structure in the alignments.

Figure 2

Alignment of the molecules used in the training set.

Figure 3

Graph of experimental versus predicted pIC₅₀ of the training set and the test set using CoMFA (a) and CoMSIA (b).

Figure 3

Graph of experimental versus predicted pIC₅₀ of the training set and the test set using CoMFA (a) and CoMSIA (b).

Figure 4

CoMFA Std* coeff contour maps illustrating steric, electrostatic fields in combination with compound 9. (a) Steric fields: green contours (80% contribution) indicate regions where bulky groups increase activity, while yellow contours (20% contribution) indicate regions where bulky groups decrease activity, and (b) Electrostatic fields: blue contours (80% contribution) indicate regions where electron-donating groups increase activity, while red contours (20% contribution) indicate regions where electron-withdrawing groups increase activity.

Figure 5

Std* coeff contour maps of CoMSIA illustrating steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields in combination with compound 9. (a) Steric contour map. Green contours refer to sterically favored regions while yellow contours refer to sterically disfavored regions. (b) Electrostatic contour map. Blue contours refer to regions where electron-donating groups are favored; red contours indicate regions where electron-withdrawing groups are favored. (c) Hydrophobic contour map. White contours (80% contribution) refer to regions where hydrophilic substituents are favored; yellow contours (20% contribution) indicate regions where hydrophobic substituents are favored. (d) Hydrogen bond donor contour map. The cyan (80% contribution) and purple (20% contribution) contours indicate favorable and unfavorable hydrogen bond donor groups. (e) Hydrogen bond acceptor contour map. The purple contours (80% contribution) for hydrogen bond acceptor groups increase activity, red contours (20% contribution) indicate the disfavored region.

Figure 6

MOLCAD Robbin surfaces structure of selected compound 9 in complex with the ATP pocket of P38α MAPK (PDB code: 3LHJ). Key residues and hydrogen bonds are labeled. The alpha helices are shown as yellow helices or cylinders, while beta sheets are shown as blue arrows and the loop regions as red tubes.

Figure 7

The MOLCAD Robbin and Multi-Channel surfaces structure displayed with cavity depth (a), electrostatic (b) and lipophilic (c) potential surfaces of the ATP pocket of p38α MAPK within the compound 9. The cavity depth color ramp ranges from blue (low depth values = outside of the pocket) to light red (high depth values = cavities deep inside the pocket). The color ramp for EP ranges from red (most positive) to purple (most negative). The color ramp for LP ranges from brown (highest lipophilic area of the surface) to blue (highest hydrophilic area).

Figure 8

Summary of structure-activity relationship revealed by 3D-QSAR and docking.

Figure 9

Graph of the predicted pIC₅₀ values of the designed inhibitors using CoMFA and CoMSIA.