The Binding Prediction of 6-Paradol and its Derivatives on TRPV1 Agonist as a New Compound for Treating Painful Diabetic Neuropathy

Abstract

<jats:p>Ginger was reported to have a suppressive effect on pain in patients with Painful Diabetic Neuropathy (PDN). Our latest study revealed that 6-shogaol, one of the ginger components, had the best affinity in the Transient Receptor Potential Vanilloid 1 (TRPV1), a key receptor in PDN). Paradol, which obtained from gingerol and shogaol metabolism, also had potent activities in several diseases, compared to the other derivatives of gingerol and shogaol. However, shogaol and paradol is very similar in chemical structure with only different in one double bond in 4-5 position. Until now there is no explanation about paradol mechanism in TRPV1. Based on this, our study was designed to predict the activity of 6-paradol and its derivatives to TRPV1 as target receptor in PDN using in-silico model. 2-paradol, 4-paradol, 6-paradol, 8-paradol and 10-paradol were used as ligands. Capsaisin, the agonist of TRPV1, was used as a native ligand in this study. TRPV1 was obtained from protein data bank (PDB). Ligand bond prediction and affinity was performed using Molegro Virtual Docker. The results showed 2-paradol, 4-paradol, 6-paradol, 8-paradol and 10- paradol had good affinity against TRPV1. These result indicated that 6-paradol and the derivatives had potential as a drug compound for PDN therapy.Keywords: ginger, 6-paradol, painful diabetic neuropathy, trpv1.</jats:p>

Natural Active Ingredients and TRPV1 Modulation: Focus on Key Chemical Moieties Involved in Ligand–Target Interaction

“…Pungent substances isolated from Zingiber officinalis , such as shogaols, gingerols, paradols and zingerone, have multiple therapeutic actions, including broad-spectrum analgesia, anti-inflammatory and anti-cancer effects [ 95 , 96 , 97 ]. They activate TRPV1 by binding the S4–S5 linker, more precisely the two residues that form a hydrogen bond with capsaicin: Thr551 and Glu571.…”

“…However, 6-paraodol established a hydrogen bond via the hydroxyl group with residues Gln143 and Glu140 and via the keto group with Gln135, while 10-paraodol presented no hydrogen bonds. All compounds presented hydrophobic interactions between the aliphatic tail and various residues of the receptor [ 97 ]. The structures of these compounds can be found in Figure 2 .…”

Ginger from Farmyard to Town: Nutritional and Pharmacological Applications

“…Among the compounds, 6-shogaol also showed potent binding affinity (-7.10 kcal/mol) for TRPV and capsaicin (-7.36 kcal/mol). Because there was no important difference in kcal/mol between 6-shogaol and the drug; therefore, it was noted that 6-shogaol could be developed as TRPV1 for the treatment of Painful Diabetic Neuropathy (PDN) (Fajrin et al, 2018;Fajrin et al, 2020b).…”

“…Another study by (Fajrin et al, 2020b) determined the potential activity of 6-paradol and its derivatives to Transient Receptor potential Vanilloid 1 (TRPV1), a target receptor in Painful Diabetic Neuropathy (PDN). In this study, 2-paradol, 4-paradol, 6-paradol, 8-paradol, and 10-paradol were used as potential inhibitors of TRPV1.…”