Potential retinoid x receptor agonists for treating Alzheimer's disease from traditional chinese medicine

Abstract

Alzheimer's disease is neurodegenerative disorder due to the accumulation of amyloid- β in the brain and causes dementia with ageing. Some researches indicate that the RXR agonist, Targretin, has also been used for treatment of Alzheimer's disease in mouse models. We investigate the potent candidates as RXR agonists from the vast repertoire of TCM compounds in TCM Database@Taiwan. The potential TCM compounds, β -lipoic acid and sulfanilic acid, had higher potent binding affinities than both 9-cis-retinoic acid and Targretin in docking simulation and have stable H-bonds with residues Arg316 and some equivalent hydrophobic contacts with residues Ala272, Gln275, Leu309, Phe313, Val342, Ile345, and Cys432 as Targretin. The carboxyl or sulfonyl hydroxide group can form a H-bond with key residue Arg316 in the docking pose, and the phenyl group next to the carboxyl or sulfonyl hydroxide group can form a π interaction with residue Phe313. Moreover, β -lipoic acid and sulfanilic acid have stable H-bonds with residue Gln275, Ser313, and residue Ala327, respectively, which may strengthen and stabilize TCM candidates inside the binding domain of RXR protein. Hence, we propose β -lipoic acid and sulfanilic acid as potential lead compounds for further study in drug development process with the RXR protein against Alzheimer's disease.

Figure 1

Disordered amino acids predicted by PONDR-Fit and sequence alignment with disordered residues (yellow regions) and residues in the binding domain (magenta regions).

Figure 2

Chemical scaffold of controls and two TCM candidates with their scoring function and sources.

Figure 3

Docking pose of RXR protein complexes with (a) 9-cis-retinoic acid, (b) Targretin, (c) β-lipoic acid, and (d) sulfanilic acid.

Figure 4

Root-mean-square deviations in units of nm and total energies over 20 ns MD simulation for RXR protein complexes with Targretin, β-lipoic acid, and sulfanilic acid.

Figure 5

Variation of (a) total solvent accessible surface area, (b) hydrophobic surface area, and (c) hydrophilic surface area over 20 ns MD simulation for RXR protein complexes with Targretin, β-lipoic acid, and sulfanilic acid.

Figure 6

Distance matrices consisting of the mean smallest distance between residue pairs for RXR protein complexes with (a) Targretin, (b) β-lipoic acid, and (c) sulfanilic acid. Residues 1–110 in y-axis correspond to residues 132–241. Residues 111–302 in y-axis correspond to residues 264–455.

Figure 7

(a) Root-mean-square deviation value (upper left half) and graphical depiction of the clusters with cutoff 0.11 nm (lower right half) for RXR protein complexes with Targretin. (b) Docking poses of middle RMSD structure in the major cluster for RXR protein complexes with Targretin. (c) Distances of hydrogen bonds with common residues during 20 ns MD simulation.

Figure 8

(a) Root-mean-square deviation value (upper left half) and graphical depiction of the clusters with cutoff 0.11 nm (lower right half) for RXR protein complexes with β-lipoic acid. (b) Docking poses of middle RMSD structure in the major cluster for RXR protein complexes with β-lipoic acid. (c) Distances of hydrogen bonds with common residues during 20 ns MD simulation.

Figure 9

(a) Root-mean-square deviation value (upper left half) and graphical depiction of the clusters with cutoff 0.11 nm (lower right half) for RXR protein complexes with sulfanilic acid. (b) Docking poses of middle RMSD structure in the major cluster for RXR protein complexes with sulfanilic acid. (c) Distances of hydrogen bonds with common residues during 20 ns MD simulation.

Figure 10

Docking poses of middle RMSD structure in the major cluster for RXR protein complexes drawn by LIGPLOT program.