Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Haichun, Zhu, Yitian, Wang, Ting, Qi, Jin, Liu, Xuming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222779/
https://www.ncbi.nlm.nih.gov/pubmed/30314397
http://dx.doi.org/10.3390/molecules23102612
_version_ 1783369286485540864
author Liu, Haichun
Zhu, Yitian
Wang, Ting
Qi, Jin
Liu, Xuming
author_facet Liu, Haichun
Zhu, Yitian
Wang, Ting
Qi, Jin
Liu, Xuming
author_sort Liu, Haichun
collection PubMed
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.
format Online
Article
Text
id pubmed-6222779
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-62227792018-11-13 Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae Radix Liu, Haichun Zhu, Yitian Wang, Ting Qi, Jin Liu, Xuming Molecules Article 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. MDPI 2018-10-11 /pmc/articles/PMC6222779/ /pubmed/30314397 http://dx.doi.org/10.3390/molecules23102612 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Haichun
Zhu, Yitian
Wang, Ting
Qi, Jin
Liu, Xuming
Enzyme-Site Blocking Combined with Optimization of Molecular Docking for Efficient Discovery of Potential Tyrosinase Specific Inhibitors from Puerariae lobatae Radix
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222779/
https://www.ncbi.nlm.nih.gov/pubmed/30314397
http://dx.doi.org/10.3390/molecules23102612
work_keys_str_mv AT liuhaichun enzymesiteblockingcombinedwithoptimizationofmoleculardockingforefficientdiscoveryofpotentialtyrosinasespecificinhibitorsfrompuerariaelobataeradix
AT zhuyitian enzymesiteblockingcombinedwithoptimizationofmoleculardockingforefficientdiscoveryofpotentialtyrosinasespecificinhibitorsfrompuerariaelobataeradix
AT wangting enzymesiteblockingcombinedwithoptimizationofmoleculardockingforefficientdiscoveryofpotentialtyrosinasespecificinhibitorsfrompuerariaelobataeradix
AT qijin enzymesiteblockingcombinedwithoptimizationofmoleculardockingforefficientdiscoveryofpotentialtyrosinasespecificinhibitorsfrompuerariaelobataeradix
AT liuxuming enzymesiteblockingcombinedwithoptimizationofmoleculardockingforefficientdiscoveryofpotentialtyrosinasespecificinhibitorsfrompuerariaelobataeradix