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3D-QSAR Studies of S-DABO Derivatives as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

[ Vol. 16 , Issue. 8 ]

Author(s):

Yueping Wang, Jie Chang, Jiangyuan Wang, Peng Zhong, Yufang Zhang, Christopher Cong Lai and Yanping He*   Pages 868 - 881 ( 14 )

Abstract:


Background: S-dihydro-alkyloxy-benzyl-oxopyrimidines (S-DABOs) as non-nucleoside reverse transcriptase inhibitors have received considerable attention during the last decade due to their high potency against HIV-1.

Methods: In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) of a series of 38 S-DABO analogues developed in our lab was studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The Docking/MMFF94s computational protocol based on the co-crystallized complex (PDB ID: 1RT2) was used to determine the most probable binding mode and to obtain reliable conformations for molecular alignment. Statistically significant CoMFA (q2=0.766 and r2=0.949) and CoMSIA (q2=0.827 and r2=0.974) models were generated using the training set of 30 compounds on the basis of hybrid docking-based and ligand-based alignment.

Results: The predictive ability of CoMFA and CoMSIA models was further validated using a test set of eight compounds with predictive r2 pred values of 0.843 and 0.723, respectively.

Conclusion: The information obtained from the 3D contour maps can be used in designing new SDABO derivatives with improved HIV-1 inhibitory activity.

Keywords:

3D-QSAR, CoMFA, CoMSIA, NNRTIs, S-DABOs, docking.

Affiliation:

Department of Applied Chemistry, Faculty of Science, Kunming University of Science and Technology, Kunming, Yunnan, 650500, Department of Applied Chemistry, Faculty of Science, Kunming University of Science and Technology, Kunming, Yunnan, 650500, Key Laboratory of Medicinal Chemistry for Natural Resource, (Ministry of Education), School of Chemical Science and Technology, Yunnan University, Kunming Yunnan, 650091, Department of Applied Chemistry, Faculty of Science, Kunming University of Science and Technology, Kunming, Yunnan, 650500, Key Laboratory of Medicinal Chemistry for Natural Resource, (Ministry of Education), School of Chemical Science and Technology, Yunnan University, Kunming Yunnan, 650091, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, Key Laboratory of Medicinal Chemistry for Natural Resource, (Ministry of Education), School of Chemical Science and Technology, Yunnan University, Kunming Yunnan, 650091

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