Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae Radix

Enzyme inhibitors from natural products are becoming an attractive target for drug discovery and development; however, separating enzyme inhibitors from natural-product extracts is highly complex. In this study, we developed a strategy based on tyrosinase-site blocking ultrafiltration integrated wit...

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Main Authors: Haichun Liu, Yitian Zhu, Ting Wang, Jin Qi, Xuming Liu
Format: Article
Language:English
Published: MDPI AG 2018-10-01
Series:Molecules
Subjects:
Online Access:http://www.mdpi.com/1420-3049/23/10/2612
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author Haichun Liu
Yitian Zhu
Ting Wang
Jin Qi
Xuming Liu
author_facet Haichun Liu
Yitian Zhu
Ting Wang
Jin Qi
Xuming Liu
author_sort Haichun Liu
collection DOAJ
description Enzyme inhibitors from natural products are becoming an attractive target for drug discovery and development; however, separating enzyme inhibitors from natural-product extracts is highly complex. In this study, we developed a strategy based on tyrosinase-site blocking ultrafiltration integrated with HPLC-QTOF-MS/MS and optimized molecular docking to screen tyrosinase inhibitors from Puerariae lobatae Radix extract. Under optimized ultrafiltration parameters, we previously used kojic acid, a known tyrosinase inhibitor, to block the tyrosinase active site in order to eliminate false-positive results. Using this strategy, puerarin, mirificin, daidzin and genistinc were successfully identified as potential ligands, and after systematic evaluation by several docking programs, the rank of the identified compounds predicted by computational docking was puerarin > mirificin > kojic acid > daidzin ≈ genistin, which agreed with the results of tyrosinase-inhibition assays. Structure-activity relationships indicated that C-glycosides showed better tyrosinase inhibition as compared with O-glycosides, with reduced inhibition achieved through the addition of glycosyl, which provides ideas about the screen of leading compounds and structural modification.
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spelling doaj.art-6c79814b68674539a5833d3c51006a692022-12-22T01:37:18ZengMDPI AGMolecules1420-30492018-10-012310261210.3390/molecules23102612molecules23102612Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae RadixHaichun Liu0Yitian Zhu1Ting Wang2Jin Qi3Xuming Liu4Jiangsu key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaJiangsu key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaJiangsu key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaJiangsu key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, ChinaSchool of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, ChinaEnzyme inhibitors from natural products are becoming an attractive target for drug discovery and development; however, separating enzyme inhibitors from natural-product extracts is highly complex. In this study, we developed a strategy based on tyrosinase-site blocking ultrafiltration integrated with HPLC-QTOF-MS/MS and optimized molecular docking to screen tyrosinase inhibitors from Puerariae lobatae Radix extract. Under optimized ultrafiltration parameters, we previously used kojic acid, a known tyrosinase inhibitor, to block the tyrosinase active site in order to eliminate false-positive results. Using this strategy, puerarin, mirificin, daidzin and genistinc were successfully identified as potential ligands, and after systematic evaluation by several docking programs, the rank of the identified compounds predicted by computational docking was puerarin > mirificin > kojic acid > daidzin ≈ genistin, which agreed with the results of tyrosinase-inhibition assays. Structure-activity relationships indicated that C-glycosides showed better tyrosinase inhibition as compared with O-glycosides, with reduced inhibition achieved through the addition of glycosyl, which provides ideas about the screen of leading compounds and structural modification.http://www.mdpi.com/1420-3049/23/10/2612affinity-ultrafiltration-MSmolecular dockingtyrosinase inhibitors
spellingShingle Haichun Liu
Yitian Zhu
Ting Wang
Jin Qi
Xuming Liu
Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae Radix
Molecules
affinity-ultrafiltration-MS
molecular docking
tyrosinase inhibitors
title Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae Radix
title_full Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae Radix
title_fullStr Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae Radix
title_full_unstemmed Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae Radix
title_short Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae Radix
title_sort enzyme site blocking combined with optimization of molecular docking for efficient discovery of potential tyrosinase specific inhibitors from puerariae lobatae radix
topic affinity-ultrafiltration-MS
molecular docking
tyrosinase inhibitors
url http://www.mdpi.com/1420-3049/23/10/2612
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