Citation: Hai-Yan ZHOU, Yuan-Yuan LI, Jing LI. 3D-QSAR Analysis of Naphthyltriazole (Lesinurad) Analogs as Potent Inhibitors of Urate Transporter 1[J]. Chinese Journal of Structural Chemistry, ;2020, 39(3): 421-436. doi: 10.14102/j.cnki.0254-5861.2011-2469 shu

3D-QSAR Analysis of Naphthyltriazole (Lesinurad) Analogs as Potent Inhibitors of Urate Transporter 1

School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China

Corresponding author: Jing LI, lij@scut.edu.cn
Received Date: 24 May 2019
Accepted Date: 16 September 2019

Fund Project: the Science and Technology Project of Guangdong Province 2015A020211005the Guangzhou Science Technology and Innovation Commission 201704020036the Fundamental Research Funds for The Central Universities 2019MS090

Figures(5)

To obtain useful information for identifying inhibitors of urate transporter 1 (URAT1), three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was conducted for a series of lesinurad analogs via Topomer comparative molecular field analysis (CoMFA). A 3D-QSAR model was established using a training set of 51 compounds and externally validated with a test set of 17 compounds. The Topomer CoMFA model obtained (q² = 0.976, r² = 0.990) was robust and satisfactory. Subsequently, seven compounds with significant URAT1 inhibitory activity were designed according to the contour maps produced by the Topomer CoMFA model.
- 3D-QSAR,
- Topomer CoMFA,
- URAT1 inhibitors
1. [1]
  Perez-Ruiz, F.; Marimon, E.; Chinchilla, S. P. Hyperuricaemia with deposition: latest evidence and therapeutic approach. Ther. Adv. Musculoskelet Dis. 2015, 7, 225−233. doi: 10.1177/1759720X15599734
2. [2]
  Punzi, L.; Scanu, A.; Ramonda, R.; Oliviero, F. Gout as autoinflammatory disease: new mechanisms for more appropriated treatment targets. Autoimmun Rev. 2012, 12, 66−71. doi: 10.1016/j.autrev.2012.07.024
3. [3]
  Terkeltaub, R.; Bushinsky, D. A.; Becker, M. A. Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics. Arthritis Res. Ther. 2006, 8, 1−4.
4. [4]
  Tan, P. K.; Farrar, J. E.; Gaucher, E. A.; Miner, J. N. Coevolution of URAT1 and uricase during primate evolution: implications for serum urate homeostasis and gout. Mol. Biol. Evol. 2016, 33, 2193−2200. doi: 10.1093/molbev/msw116
5. [5]
  Forcet, C.; Stein, E.; Pays, L.; Corset, V.; Llambi, F.; Tessier-Lavigne, M.; Mehlen, P. Netrin-1 mediated axon outgrowth requires deleted in colorectal cancer-dependent MAPK activation. Nature 2002, 417, 443−447. doi: 10.1038/nature748
6. [6]
  Hoy, S. M. Lesinurad: first global approval. Drugs 2016, 76, 509−516. doi: 10.1007/s40265-016-0550-y
7. [7]
  Tan, P. K.; Liu, S.; Gunic, E.; Miner, J. N. Discovery and characterization of verinurad, a potent and specific inhibitor of URAT1 for the treatment of hyperuricemia and gout. Sci. Rep. 2017, 7, 665−676. doi: 10.1038/s41598-017-00706-7
8. [8]
  Poiley, J.; Steinberg, A. S.; Choi, Y. J.; Davis, C. S.; Martin, R. L.; McWherter, C. A.; Boudes, P. F. A randomized, double-blind, active- and placebo-controlled efficacy and safety study of arhalofenate for reducing flare in patients with gout. Arthritis Rheumatol. 2016, 68, 2027−2034. doi: 10.1002/art.39684
9. [9]
  Edwards, N. L.; So, A. Emerging therapies for gout. Rheum. Dis. Clin. N. Am. 2014, 40, 375−387. doi: 10.1016/j.rdc.2014.01.013
10. [10]
  Mandal, A. K.; Mercado, A.; Foster, A.; Zandi-Nejad, K.; Mount, D. B. Uricosuric targets of tranilast. Pharmacol Res. Perspect. 2017, 5, 291−301.
11. [11]
  Pan, Y.; Kong, L. D. Urate transporter URAT1 inhibitors: a patent review (2012-2015). Expert Opin. Ther. 2016, 26, 1129−1138. doi: 10.1080/13543776.2016.1213243
12. [12]
  Peng, J.; Hu, Q.; Gu, C.; Liu, B.; Jin, F.; Yuan, J.; Feng, J.; Zhang, L.; Lan, J.; Dong, Q.; Cao, G. Discovery of potent and orally bioavailable inhibitors of human uric acid transporter 1 (hURAT1) and binding mode prediction using homology model. Bioorg. Med. Chem. Lett. 2016, 26, 277−282. doi: 10.1016/j.bmcl.2015.12.040
13. [13]
  Cai, W.; Liu, W.; Zhang, S.; Wang, J.; Zhao, G. Design, synthesis and bioactivity of highly sterically congested flexible uric acid transporter 1 (URAT1) inhibitors. Chin. J. Org. Chem. 2017, 37, 2303−2314. doi: 10.6023/cjoc201704038
14. [14]
  Tian, H.; Liu, W.; Zhou, Z.; Shang, Q.; Liu, Y.; Xie, Y.; Liu, C.; Xu, W.; Tang, L.; Wang, J.; Zhao, G. Discovery of a flexible triazolylbutanoic acid as a highly potent uric acid transporter 1 (URAT1) inhibitor. Molecules 2016, 21, 1543−1548. doi: 10.3390/molecules21111543
15. [15]
  Cai, W.; Liu, W.; Xie, Y.; Wu, J.; Liu, Y.; Liu, C.; Xu, W.; Tang, L.; Wang, J.; Zhao, G. Design, synthesis and biological activity of tetrazole-bearing uric acid transporter 1 inhibitors. Chem. Res. Chin. U. 2017, 33, 49−60. doi: 10.1007/s40242-017-6351-3
16. [16]
  Peng, J.; Hu, Q.; Gu, C.; Liu, B.; Jin, F.; Yuan, J.; Feng, J.; Zhang, L.; Lan, J.; Dong, Q. Discovery of potent and orally bioavailable inhibitors of human uric acid transporter 1 (hURAT1) and binding mode prediction using homology model. Bioorg. Med. Chem. Lett. 2016, 26, 277−282. doi: 10.1016/j.bmcl.2015.12.040
17. [17]
  Cramer, R. D. Topomer CoMFA: a design methodology for rapid lead optimization. J. Med. Chem. 2003, 46, 374−388. doi: 10.1021/jm020194o
18. [18]
  Xu, C.; Ren, Y. Molecular modeling studies of [6, 6, 5] tricyclic fused oxazolidinones as fxa inhibitors using 3D-QSAR, topomer CoMFA, molecular docking and molecular dynamics simulations. Bioorg. Med. Chem. Lett. 2015, 25, 4522−4528. doi: 10.1016/j.bmcl.2015.08.070
19. [19]
  Halder, A. K.; Amin, S. A.; Jha, T.; Gayen, S. Insight into the structural requirements of pyrimidine-based phosphodiesterase 10A (PDE10A) inhibitors by multiple validated 3D-QSAR approaches. SAR QSAR Environ. Res. 2017, 28, 253−273. doi: 10.1080/1062936X.2017.1302991
20. [20]
  Zhao, T. T.; Zhao, Z. A.; Lu, F. T.; Chang, S.; Zhang, J. J.; Pang, J. X.; Tian, Y. X. Two- and three-dimensional QSAR studies on hURAT1 inhibitors with flexible linkers: topomer CoMFA and HQSAR. Mol. Divers. 2019.https://doi.org/10.1007/s11030-019-09936-5 doi: 10.1007/s11030-019-09936-5
21. [21]
  Leonard, J. T.; Roy, K. On Selection of training and test sets for the development of predictive QSAR models. QSAR Comb. Sci. 2006, 25, 235−251. doi: 10.1002/qsar.200510161
22. [22]
  Li, S.; Li, M.; Chao, R.; Dong, C.; Jun, M.; Jing, C.; Tai, L.; Qing, L. 3D-QSAR studies on 4-([1, 2, 4]triazolo[1, 5-α]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole analogues as potent inhibitors of transforming growth factor-β typeⅠreceptor kinase. Chin. J. Struct. Chem. 2018, 37, 517−530.
23. [23]
  Xiao, C.; Yu, M.; Zhong, Z.; Ling, Z.; Ying, L. Molecular docking, 3D-QSAR and molecular dynamics simulation studies of substituted pyrimidines as selective covalent janus kinase 3 inhibitors. Chin. J. Struct. Chem. 2018, 37, 839−853.
24. [24]
  Lu, W.; Yan, Z.; Shuai, L.; Ya, C.; Tao, L.; Hai, L. Molecular docking and 3D-QSAR studies on a series of fused heterocyclic amides as B-Raf inhibitors. Chin. J. Struct. Chem. 2017, 36, 1568−1585.
25. [25]
  Xiang, Y.; Hou, Z.; Zhang, Z. Pharmacophore and qsar studies to design novel histone deacetylase 2 inhibitors. Chem. Biol. Drug Des. 2012, 79, 760−770. doi: 10.1111/j.1747-0285.2012.01341.x
26. [26]
  Yang, Q.; Zhang, S. P.; Zhao, S. P. 3D-QSAR studies on a series of indoleamide derivatives as antiplasmodial drugs. Chin. J. Struct. Chem. 2018, 37, 1015−1024.
27. [27]
  Cramer, R. D. 3^rd. Patterson, D. E.; Bunce, J. D. Recent advances in comparative molecular field analysis (CoMFA). Pro. Clin. Biol. Res. 1989, 291, 161−165.
28. [28]
  Golbraikh, A.; Tropsha, A. Beware of q². J. Mol. Grap. Model. 2002, 20, 269−276. doi: 10.1016/S1093-3263(01)00123-1
29. [29]
  Vrontaki, E.; Melagraki, G.; Mavromoustakos, T.; Afantitis, A. Searching for anthranilic acid-based thumb pocket 2 HCV NS5B polymerase inhibitors through a combination of molecular docking, 3D-QSAR and virtual screening. J. Enzym Inhib. Med. Ch. 2016, 31, 38−52.
30. [30]
  Hao, C. Z.; Xia, S. W.; Wang, H.; Xue, J.; Yu, L. M. Using 3D-QSAR and molecular docking insight into inhibitors binding with complex-associated kinases CDK8. J. Mol. Struct. 2018, 1173, 498−511. doi: 10.1016/j.molstruc.2018.05.072
31. [31]
  Roy, K.; Kar, S. The r_m² metrics and regression through origin approach: reliable and useful validation tools for predictive QSAR models (commentary on 'is regression through origin useful in external validation of QSAR models?'). Eur. J. Pharm. Sci. 2014, 62, 111−114. doi: 10.1016/j.ejps.2014.05.019
1. [1]
  Junjun Huang , Ran Chen , Yajian Huang , Hang Zhang , Anran Zheng , Qing Xiao , Dan Wu , Ruxia Duan , Zhi Zhou , Fei He , Wei Yi . Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selective α_1D/1A-adrenoceptor antagonist and homology modelling. Chinese Chemical Letters, 2024, 35(11): 109594-. doi: 10.1016/j.cclet.2024.109594
2. [2]
  Shiqi Xu , Zi Ye , Shuang Shang , Fengge Wang , Huan Zhang , Lianguo Chen , Hao Lin , Chen Chen , Fang Hua , Chong-Jing Zhang . Pairs of thiol-substituted 1,2,4-triazole-based isomeric covalent inhibitors with tunable reactivity and selectivity. Chinese Chemical Letters, 2024, 35(7): 109034-. doi: 10.1016/j.cclet.2023.109034
3. [3]
  Han Yuan , Fengcai Zhang , Hongzhe Huang , Jiafei Wu , Yi Yang , Wanyi Huang , Dongjing Yang , Zhuoming Li , Zhe Li , Ling Huang , Yi-You Huang , Hai-Bin Luo , Lei Guo . Discovery of 3-trifluoromethyl-substituted pyrazoles as selective phosphodiesterase 10A inhibitors for orally attenuating isoprenaline-induced cardiac hypertrophy. Chinese Chemical Letters, 2025, 36(4): 109965-. doi: 10.1016/j.cclet.2024.109965
4. [4]
  Yulong Shi , Fenbei Chen , Mengyuan Wu , Xin Zhang , Runze Meng , Kun Wang , Yan Wang , Yuheng Mei , Qionglu Duan , Yinghong Li , Rongmei Gao , Yuhuan Li , Hongbin Deng , Jiandong Jiang , Yanxiang Wang , Danqing Song . Chemical construction and anti-HCoV-OC43 evaluation of novel 10,12-disubstituted aloperine derivatives as dual cofactor inhibitors of TMPRSS2 and SR-B1. Chinese Chemical Letters, 2024, 35(5): 108792-. doi: 10.1016/j.cclet.2023.108792
5. [5]
  Hai-Yang Song , Jun Jiang , Yu-Hang Song , Min-Hang Zhou , Chao Wu , Xiang Chen , Wei-Min He . Supporting-electrolyte-free electrochemical [2 + 2 + 1] annulation of benzo[d]isothiazole 1,1-dioxides, N-arylglycines and paraformaldehyde. Chinese Chemical Letters, 2024, 35(6): 109246-. doi: 10.1016/j.cclet.2023.109246
6. [6]
  Jinge Zhu , Ailing Tang , Leyi Tang , Peiqing Cong , Chao Li , Qing Guo , Zongtao Wang , Xiaoru Xu , Jiang Wu , Erjun Zhou . Chlorination of benzyl group on the terminal unit of A₂-A₁-D-A₁-A₂ type nonfullerene acceptor for high-voltage organic solar cells. Chinese Chemical Letters, 2025, 36(1): 110233-. doi: 10.1016/j.cclet.2024.110233
7. [7]
  Jiayu Huang , Kuan Chang , Qi Liu , Yameng Xie , Zhijia Song , Zhiping Zheng , Qin Kuang . Fe-N-C nanostick derived from 1D Fe-ZIFs for Electrocatalytic oxygen reduction. Chinese Journal of Structural Chemistry, 2023, 42(10): 100097-100097. doi: 10.1016/j.cjsc.2023.100097
8. [8]
  Huan Hu , Ying Zhang , Shi-Shuang Huang , Zhi-Gang Li , Yungui Liu , Rui Feng , Wei Li . Temperature- and pressure-responsive photoluminescence in a 1D hybrid lead halide. Chinese Journal of Structural Chemistry, 2024, 43(10): 100395-100395. doi: 10.1016/j.cjsc.2024.100395
9. [9]
  Yuexi Guo , Zhaoyang Li , Jingwei Dai . Charlie and the 3D Printing Chocolate Factory. University Chemistry, 2024, 39(9): 235-242. doi: 10.3866/PKU.DXHX202309067
10. [10]
  Bairu Meng , Zongji Zhuo , Han Yu , Sining Tao , Zixuan Chen , Erik De Clercq , Christophe Pannecouque , Dongwei Kang , Peng Zhan , Xinyong Liu . Design, synthesis, and biological evaluation of benzo[4,5]thieno[2,3-d]pyrimidine derivatives as novel HIV-1 NNRTIs. Chinese Chemical Letters, 2024, 35(6): 108827-. doi: 10.1016/j.cclet.2023.108827
11. [11]
  Xudong Zhao , Yuxuan Wang , Xinxin Gao , Xinli Gao , Meihua Wang , Hongliang Huang , Baosheng Liu . Anchoring thiol-rich traps in 1D channel wall of metal-organic framework for efficient removal of mercury ions. Chinese Chemical Letters, 2025, 36(2): 109901-. doi: 10.1016/j.cclet.2024.109901
12. [12]
  Jie XIE , Hongnan XU , Jianfeng LIAO , Ruoyu CHEN , Lin SUN , Zhong JIN . Nitrogen-doped 3D graphene-carbon nanotube network for efficient lithium storage. Chinese Journal of Inorganic Chemistry, 2024, 40(10): 1840-1849. doi: 10.11862/CJIC.20240216
13. [13]
  Xi Xu , Chaokai Zhu , Leiqing Cao , Zhuozhao Wu , Cao Guan . Experiential Education and 3D-Printed Alloys: Innovative Exploration and Student Development. University Chemistry, 2024, 39(2): 347-357. doi: 10.3866/PKU.DXHX202308039
14. [14]
  Qiang Zhou , Pingping Zhu , Wei Shao , Wanqun Hu , Xuan Lei , Haiyang Yang . Innovative Experimental Teaching Design for 3D Printing High-Strength Hydrogel Experiments. University Chemistry, 2024, 39(6): 264-270. doi: 10.3866/PKU.DXHX202310064
15. [15]
  Changyuan Bao , Yunpeng Jiang , Haoyin Zhong , Huaizheng Ren , Junhui Wang , Binbin Liu , Qi Zhao , Fan Jin , Yan Meng Chong , Jianguo Sun , Fei Wang , Bo Wang , Ximeng Liu , Dianlong Wang , John Wang . Synergizing 3D-printed structure and sodiophilic interface enables highly efficient sodium metal anodes. Chinese Chemical Letters, 2024, 35(11): 109353-. doi: 10.1016/j.cclet.2023.109353
16. [16]
  Chengmin Hu , Pingxuan Liu , Ziyang Song , Yaokang Lv , Hui Duan , Li Xie , Ling Miao , Mingxian Liu , Lihua Gan . Tailor-made overstable 3D carbon superstructures towards efficient zinc-ion storage. Chinese Chemical Letters, 2025, 36(4): 110381-. doi: 10.1016/j.cclet.2024.110381
17. [17]
  He Yao , Wenhao Ji , Yi Feng , Chunbo Qian , Chengguang Yue , Yue Wang , Shouying Huang , Mei-Yan Wang , Xinbin Ma . Copper-catalyzed and biphosphine ligand controlled 3,4-boracarboxylation of 1,3-dienes with carbon dioxide. Chinese Chemical Letters, 2025, 36(4): 110076-. doi: 10.1016/j.cclet.2024.110076
18. [18]
  Yuan Teng , Zichun Zhou , Jinghua Chen , Siying Huang , Hongyan Chen , Daibin Kuang . Dual atom-bridge effect promoting interfacial charge transfer in 2D/2D Cs₃Bi₂Br₉/BiOBr epitaxial heterojunction for efficient photocatalysis. Chinese Chemical Letters, 2025, 36(2): 110430-. doi: 10.1016/j.cclet.2024.110430
19. [19]
  Hualin Jiang , Wenxi Ye , Huitao Zhen , Xubiao Luo , Vyacheslav Fominski , Long Ye , Pinghua Chen . Novel 3D-on-2D g-C₃N₄/AgI._x._y heterojunction photocatalyst for simultaneous and stoichiometric production of H₂ and H₂O₂ from water splitting under visible light. Chinese Chemical Letters, 2025, 36(2): 109984-. doi: 10.1016/j.cclet.2024.109984
20. [20]
  Xiao-Hong Yi , Chong-Chen Wang . Metal-organic frameworks on 3D interconnected macroporous sponge foams for large-scale water decontamination: A mini review. Chinese Chemical Letters, 2024, 35(5): 109094-. doi: 10.1016/j.cclet.2023.109094

Get Citation

PDF

XML

Metrics

PDF Downloads(1)
Abstract views(347)
HTML views(13)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142