Molecular docking of 2-(benzimidazol-2-ylthio)-N-phenylacetamide-derived small-molecule agonists of human formyl peptide receptor 1

Abstract

Human N-formyl peptide receptor 1 (FPR1) is a G protein-coupled receptor (GPCR) involved in host defense and sensing cellular damage. Since structure-based ligand design for many GPCRs, including FPR1, is restricted by the lack of experimental three dimensional structures, homology modeling has been widely used to study GPCR-ligand binding. Indeed, receptor-ligand binding mode predictions can be derived from homology modeling with supporting ligand information. In the present work, we report comparative docking studies of 2-(benzimidazol-2-ylthio)-N-phenylacetamide derived FPR1 agonists, identified here and previously, with several known FPR1 peptide agonists in a FPR1 homology model that is based on the crystal structure of bovine rhodopsin. We found that the binding pocket of the most active molecules shares some common features with high affinity FPR1 peptide agonists, suggesting that they may bind to similar binding sites. Classification tree analysis led to the derivation of a good recognition model based on four amino acid descriptors for distinguishing FPR1 ligands from inactive analogs. Hence, the corresponding residues (Thr199, Arg201, Gly202, and Ala261) can be considered as markers of important areas in the ligand binding site. Concurrently, we identified several unique binding features of benzimidazole derivatives and showed that alkoxy-substituents of the benzimidazole ring are located within a FPR1 hole bounded by Thr199, Thr265, Ile268, and Leu271 or in a groove in the vicinity of Leu198, Arg201, Gly202, and Arg205. The understanding of these molecular features will likely prove beneficial in future design of novel FPR1 agonists based on the benzimidazole scaffold.

Fig. 1

FPR1 binding site with docked peptides Ac-QAWF and fMLF. Panel a: Position of the spherical search space in the FPR1 selected as a sphere with 11 Å radius around the Ac-QAWF Ala carbonyl carbon. Panel b: Key features of the FPR1 binding site with docking poses of Ac-QAWF reported by Movitz et al. [7] (thin sticks) and obtained by us (purple) compared with the pose of fMLF peptide (white). Arrows indicate: channel A; curved cavity B located behind the blue-colored ledge; channel C; “bottom” D of the binding site between channels A and C; and large cavity E, located between channel C and larger blue-colored ledge. See text for further details or regions A–F. Surface coloring was made according to electrostatic properties – negatively and positively charged areas are shown in red and blue, respectively

Fig. 2

Docking poses of fMLF and the two most potent benzimid-azole FPR1 agonists. Panel a. Specific interaction between Arg205 and fMLF (thick sticks) docked into the FPR1 binding site. H-bond is shown by dashed blue lines. Electrostatic ion–pair interaction is indicated by the green marker. Panel b. Docking poses of benzimidazole-derived FPR1 agonists AG-11/03 (purple) and AG-11/05 (green). H-bonds are indicated with dash lines

Fig. 3

Docking poses of alkoxy-substituted benzimidazole derivatives AG-11/03, AG-11/05, and AG-09/01 relative to the surface of the FPR1 binding site (Panel a) and amino acids Thr199, Arg201, Gly202, and Ala261 with the protein surface removed (Panel b). In Panel b, AG-11/03, AG-11/05, and AG-09/01 are shown in pink, green, and blue, respectively

Fig. 4

Classification tree obtained based on 46 initial descriptors taken from docking results

Fig. 5

Docking poses for FPR1 agonists (panels a–d) and non-active analogs (panel e) relative to the surface of the FPR1 binding site (left part) and amino acids Thr199, Arg201, Gly202, and Ala261 with the protein surface removed (right part)