Homology modeling and virtual screening studies of FGF-7 protein-a structure-based approach to design new molecules against tumor angiogenesis

Abstract

Keratinocyte growth factor (KGF) protein is a member of the fibroblast growth factor (FGF) family, which is also known as FGF-7. The FGF-7 plays an important role in tumor angiogenesis. In the present work, FGF-7 is treated as a potential therapeutic target to prevent angiogenesis in cancerous tissue. Computational techniques are applied to evaluate and validate the 3D structure of FGF-7 protein. The active site region of the FGF-7 protein is identified based on hydrophobicity calculations using CASTp and Q-site Finder active site prediction tools. The protein-protein docking study of FGF-7 with its natural receptor FGFR2b is carried out to confirm the active site region in FGF-7. The amino acid residues Asp34, Arg67, Glu116, and Thr194 in FGF-7 interact with the receptor protein (FGFR2b). A grid is generated at the active site region of FGF-7 using Glide module of Schrödinger suite. Subsequently, a virtual screening study is carried out at the active site using small molecular structural databases to identify the ligand molecules. The binding interactions of the ligand molecules, with piperazine moiety as a pharmacophore, are observed at Arg67 and Glu149 residues of the FGF-7 protein. The identified ligand molecules against the FGF-7 protein show permissible pharmacokinetic properties (ADME). The ligand molecules with good docking scores and satisfactory pharmacokinetic properties are prioritized and identified as novel ligands for the FGF-7 protein in cancer therapy.

Keywords: ADME; Angiogenesis; FGF-7; Protein–protein docking; Virtual screening.

Fig. 1

Homology model of FGF-7 protein. The FGF-7 homology model represented as cartoon. Helices are represented in pink, sheets in blue, and loops in yellow orange color as generated by the PyMOL program

Fig. 2

The binding interactions of FGF7–FGFR2b docked complex. The best docked complex from the protein–protein docking studies, prioritized on the basis of Z-rank, is presented, out of an output of 200 docked complexes. FGFR2b is represented in purple solid ribbon and FGF-7 in green. Four hydrogen bonds are shown in black dotted lines, one salt bridge in light green line, and two pi-cation interactions in orange lines

Fig. 3

Docked pictures of ligands R1–R10 with protein FGF-7 showing bonding interactions. Binding interactions of the FGF-7 protein with its ligands. The protein is represented in cyan solid ribbon form. The FGF-7 protein amino acid residues are represented in orange sticks, ligands in purple ball and stick form. The hydrogen bond interactions are represented in black. The pi-cation interactions are represented in yellow

Fig. 3

Docked pictures of ligands R1–R10 with protein FGF-7 showing bonding interactions. Binding interactions of the FGF-7 protein with its ligands. The protein is represented in cyan solid ribbon form. The FGF-7 protein amino acid residues are represented in orange sticks, ligands in purple ball and stick form. The hydrogen bond interactions are represented in black. The pi-cation interactions are represented in yellow

Fig. 3

Docked pictures of ligands R1–R10 with protein FGF-7 showing bonding interactions. Binding interactions of the FGF-7 protein with its ligands. The protein is represented in cyan solid ribbon form. The FGF-7 protein amino acid residues are represented in orange sticks, ligands in purple ball and stick form. The hydrogen bond interactions are represented in black. The pi-cation interactions are represented in yellow