The Significance of Serine of NTD-NPC1L1 for Cholesterol Binding with Compounds in Traditional Spices

Abstract

It has been proposed that Niemann-Pick C1 like-1 (NPC1L1) is an intermediate membrane protein that facilitates cholesterol absorption at enterocytes, yet it is still being unknown mechanism. The study aimed to evaluate the pharmacokinetics of anti-cholesterol in traditional spices and investigate the interactions between anti-cholesterol compounds and NPC1L1. This research analyzed binding pocket, Admet, drug-likeness, the interactions, and binding affinities by DoGSiteScorer and Depth, AdmetSAR tools, and MOE.2009 software, respectively. The interactions and binding affinities were determined by molecular docking between NPC1L1 and 18 ligands derived from spices such as Cinnamon, Bay leaf, coriander, Garlic, Red Onion, Tumeric, Indosenian Chilli Pepper. Inhibitors were docked with NPC1L1 (PDB ID: 3QNT), and a comparison was made between the results of Ezetimibe, a prescribed NPC1L1 inhibitor. The Lipinski Rule of Five aids in identifying drug-like compounds and those that are not. As an octanol-water partition coefficient log P not greater than 5, all ligand including Ezetimibe has a higher affinity for the aqueous phase. 11 out of 18 inhibitors were well absorbed and distributed by forecasting oral bioavailability. Quercetin, Curcumin, and 6-Gingerol from onion, turmeric, and ginger are the potential to inhibit cholesterol absorption in the small intestine. These three highest binding energy ligands (-14.0320 to -12.3998 kcal/mol) had high binding affinities as Ezetimibe (-15.5075 kcal/mol). High binding affinities of Ezetimibe and these ligands interact at almost in the exact locations of the N-terminal domain. Through Ser_102 of N-terminal domain NPC1L1 binding with the ligands, we suggest that traditional spices of three ligands could interfere with cholesterol absorption at the early stages.