Understanding molecular interactions between scavenger receptor A and its natural product inhibitors through molecular modeling studies

Abstract

Scavenger receptor A (SRA), as an immune regulator, has been shown to play important roles in lipid metabolism, cardiovascular diseases, and pathogen recognition. Several natural product inhibitors of SRA have been studied for their potential application in modulating SRA functions. To understand the binding mode of these inhibitors on SRA, we conducted systematic molecular modeling studies in order to identify putative binding domain(s) that may be responsible for their recognition to the receptor as well as their inhibitory activity. Treatment of SRA with one of the natural product inhibitors, rhein, led to significant dissociation of SRA oligomers to its trimer and dimer forms, which further supported our hypothesis on their putative mechanism of action. Such information is believed to shed light on design of more potent inhibitors for the receptor in order to develop potential therapeutics through immune system modulation.

Keywords: Binding modes; Docking; Inhibitor; Molecular dynamics simulation; Natural products; SRA.

Fig. 1

Chemical structures of natural product SRA inhibitors.

Fig. 2

Lowest energy conformation of four natural product SRA inhibitors. A) Tannic acid; B) Sennoside B; C) Rhein; and D) Danthron.

Fig. 3

Schematic of the structural domains of Scavenger Receptor A and MARCO.

Fig. 4

Docking modes of tannic acid (in balls and sticks) on SRA domain monomer (cartoon representation). Amino acid residues involved in putative interactions are shown in green sticks representation: A) Site 1; B) Site 2; C) Site 3; D) Site 4.

Fig. 5

Most preferred docking mode of sennoside B (in balls and sticks) on SRA domain monomer (cartoon representation). Amino acid residues involved in putative interactions are shown in green sticks representation.

Fig. 6

Docking modes of danthron (in balls and sticks) on Site 3 of SRA domain monomer (cartoon representation). Amino acid residues involved in putative interactions are shown in green sticks representation.

Fig. 7

Most preferred docking mode of tannic acid (in balls and sticks) on SRA domain dimer (site 3, cartoon representation). Amino acid residues involved in putative interactions are shown in green sticks.

Fig. 8

Most preferred docking mode of sennoside B (in balls and sticks) on SRA domain dimer (site 3, cartoon representation). Amino acid residues involved in putative interactions are shown in green sticks representation.

Fig. 9

Electrostatic potential map of dimeric SRA model. Highest HINT scored docking solutions for at the most preferred docking mode for each ligand (ball and stick representations) A) Tannic acid; B) Sennoside B; C) Rhein, and D) Danthron.

Fig. 10

Root-mean-square-deviation (RMSD) of the protein backbone atoms of SRA dimer model and the four complexes.

Fig. 11

Binding pose for each ligand (ball and stick representations –left and 2D –right) after MD simulations– A) Tannic acid; B) Sennoside B; C) Rhein, and D) Danthron.

Fig. 11

Binding pose for each ligand (ball and stick representations –left and 2D –right) after MD simulations– A) Tannic acid; B) Sennoside B; C) Rhein, and D) Danthron.

Fig. 12

Treatment with rhein affects the oligomerization of SRA. The culture media containing secreted SRA protein was incubated with or without rhein at concentrations indicated, followed by analysis using native PAGE. Lane 1: control; lane 2: 100 μM rhein treated; lane 3: 300 μM rhein treated; lane 4: 1000 μM rhein treated; lane 5: native marker.