NDLI: Accurate Prediction of Glucuronidation of Structurally Diverse Phenolics by Human UGT1A9 Using Combined Experimental and In Silico Approaches

Content Provider	Springer Nature Link
Author	Wu, Baojian Wang, Xiaoqiang Zhang, Shuxing Hu, Ming
Copyright Year	2012
Abstract	Catalytic selectivity of human UGT1A9, an important membrane-bound enzyme catalyzing glucuronidation of xenobiotics, was determined experimentally using 145 phenolics and analyzed by 3D-QSAR methods.Catalytic efficiency of UGT1A9 was determined by kinetic profiling. Quantitative structure activity relationships were analyzed using CoMFA and CoMSIA techniques. Molecular alignment of substrate structures was made by superimposing the glucuronidation site and its adjacent aromatic ring to achieve maximal steric overlap. For a substrate with multiple active glucuronidation sites, each site was considered a separate substrate.3D-QSAR analyses produced statistically reliable models with good predictive power (CoMFA: q$^{2}$ = 0.548, r$^{2}$ = 0.949, r pred 2 = 0.775; CoMSIA: q$^{2}$ = 0.579, r$^{2}$ = 0.876, r pred 2 = 0.700). Contour coefficient maps were applied to elucidate structural features among substrates that are responsible for selectivity differences. Contour coefficient maps were overlaid in the catalytic pocket of a homology model of UGT1A9, enabling identification of the UGT1A9 catalytic pocket with a high degree of confidence.CoMFA/CoMSIA models can predict substrate selectivity and in vitro clearance of UGT1A9. Our findings also provide a possible molecular basis for understanding UGT1A9 functions and substrate selectivity.
Starting Page	1544
Ending Page	1561
Page Count	18
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	29
Issue Number	6
e-ISSN	1573904X
Language	English
Publisher	Springer US
Publisher Date	2012-02-03
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	CoMFA CoMSIA glucuronidation homology modeling UGT1A9 Pharmacy Medical Law Pharmacology/Toxicology Biomedical Engineering Biochemistry
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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