Conformational characterization of ipomotaosides and their recognition by COX-1 and 2

Abstract

The aerial parts of Ipomoea batatas are described herein to produce four new resin glycosides, designated as ipomotaosides A, B, C, and D. Ipomotaoside A was found to present inhibitory activity on both cyclooxygenases. However, the conformational elucidation of these molecules may be difficult due to their high flexibility. In this context, the current work presents a conformational characterization of ipomotaosides A-D in aqueous and nonaqueous solvents. The employed protocol includes metadynamics evaluation and unrestrained molecular dynamics simulations (MD). The obtained data provided structural models for the ipomotaosides in good agreement with previous ROESY distances measured in pyridine. Accordingly, the most abundant conformation of ipomotaoside A in solution was employed in flexible docking studies, providing a structural basis for the compound's inhibition of COX enzymes. The so-obtained complex supports resin glycosides' role as original scaffolds for future studies, aiming at structural optimization and development of potential new anti-inflammatory agents.

Figure 1

Representations of the ipomotaosides characterized in the current work.

Figure 2

(A,B) Conformational behavior of α-l-Rha-(1→2)-β-d-Fuc and α-l-Rha-(1→4)-α-l-Rha linkages, as obtained from metadynamics in both pyridine and water; (C,D) Distribution of Φ and Ψ dihedral angles during simulations associated with the glycosidic linkages of isolated disaccharides. The aqueous solution is represented as black and the nonaqueous solution (pyridine) is indicated as red.

Figure 3

Root mean square fluctuation (RMSF) for ipomotaoside A macrocycle and acyl chains. A tridimensional representation of each structure is highlighted in green, at the top, and the corresponding RMSF is at the bottom. Aqueous solution is represented in black and pyridine is indicated in red.

Figure 4

Complexes obtained for PGG₂ (A,C) and ipomotaoside 1 (B,D) with COX-1 as derived from docking calculations. Heme group is highlighted in yellow. 2D images, generated with the PoseView server [17], present only interactions between the ligand and amino acid residues. Common amino acid residues between PGG₂-COX-1 are indicated in red.