Uroporphyrinogen Decarboxylase as a Potential Target for Specific Components of Traditional Chinese Medicine: A Virtual Screening and Molecular Dynamics Study

Yung-An Tsou,Hung-Che Lin,Kuan-Chung Chen,Calvin Yu-Chian Chen,Su-Sen Chang,Joseph J. Barchi

doi:10.1371/journal.pone.0050087

Abstract

Uroporphyrinogen decarboxylase (UROD) has been suggested as a protectant against radiation for head and neck cancer (HNC). In this study, we employed traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw/) to screen for drug-like candidates with potential UROD inhibition characteristics using virtual screening techniques. Isopraeroside IV, scopolin, and nodakenin exhibited the highest Dock Scores, and were predicted to have good Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Two common moieties, 2H-chromen-2-one and glucoside, were observed among the top TCM candidates. Cross comparison of the docking poses indicated that candidates formed stable interactions with key binding and catalytic residues of UROD through these two moieties. The 2H-chromen-2-one moiety enabled pi-cation interactions with Arg37 and H-bonds with Tyr164. The glucoside moiety was involved in forming H-bonds with Arg37 and Asp86. From our computational results, we propose isopraeroside IV, scopolin, and nodakenin as ligands that might exhibit drug-like inhibitory effects on UROD. The glucoside and 2H-chromen-2-one moieties may potentially be used for designing inhibitors of UROD.

Highlights

Head and neck cancer (HNC), one of the most common malignancies worldwide [1,2], refers to cancer originating from the upper aerodigestive tract [3]
In vivo suppression of the tumor-forming ability of HNC cells and delayed growth of formed tumor xenografts in mice were reported [5]. These findings suggest that Uroporphyrinogen decarboxylase (UROD) may be a potential drug target for controlling HNC
Structural comparisons reveal that the traditional Chinese medicine (TCM) candidates share two common moieties, 2Hchromen-2-one and glucoside

Summary

Introduction

Head and neck cancer (HNC), one of the most common malignancies worldwide [1,2], refers to cancer originating from the upper aerodigestive tract [3]. Uroporphyrinogen decarboxylase (UROD) has been implicated as a tumor-selective protectant for HNC against radiation [4]. In vivo suppression of the tumor-forming ability of HNC cells and delayed growth of formed tumor xenografts in mice were reported [5]. These findings suggest that UROD may be a potential drug target for controlling HNC. The catalytic process of decarboxylation starts with the acetate on the asymmetric ring of the natural substrate, uroporphyrinogen III, under physiological substrate concentrations [13,14]. Molecular dynamics (MD) simulations were employed to examine the stabilizing interactions within each complex under a dynamic state simulating physiological conditions

Results and Discussion

Conclusion

Materials and Methods