Two- and three-dimensional QSAR studies on hURAT1 inhibitors with flexible linkers: topomer CoMFA and HQSAR
- 38 Downloads
hURAT1 (human urate transporter 1) is a successful target for hyperuricemia. Recently, the modification work on hURAT1 inhibitors showed that the flexible linkers would benefit biological activity. The study aimed to investigate the contribution of the linkers and give modification strategies on this kind of structures based on QSAR models (HQSAR and topomer CoMFA). The most effective HQSAR and topomer CoMFA models were generated by applying the training set containing 63 compounds, with the cross-validated q2 values of 0.869/0.818 and the non-cross-validated correlation coefficients r2 of 0.951/0.978, respectively. The Y-randomization test was applied to ensure the robustness of the models. The external predictive correlation coefficient (r pred 2 ) grounded on the external test set (21 compounds) of two models was 0.910 and 0.907, respectively. In addition, the models were validated by Golbraikh–Tropsha and Roy methods, as well as other statistical metrics. The results showed that both models were reliable. Topomer CoMFA steric/electrostatic contours and HQSAR atomic contribution maps illustrated the structural features which governed their inhibitory potency. The dependable results could provide important insights to guide the designing of more potential hURAT1 inhibitors.
KeywordsHyperuricemia hURAT1 inhibitors HQSAR Topomer COMFA
This work was supported by the Natural Science Foundation of China (No: 81773794), Natural Science Foundation of Guangdong Province (2018A0303130088) and the Foundation of science and technology of Guangdong (2014A020210013), China.
Compliance with ethical standards
Conflict of interest
The authors affirm that there are no conflicts of interest.
- 2.Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castaneda-Sanabria J, Coyfish M, Guillo S, Jansen TL, Janssens H, Liote F, Mallen C, Nuki G, Perez-Ruiz F, Pimentao J, Punzi L, Pywell T, So A, Tausche AK, Uhlig T, Zavada J, Zhang W, Tubach F, Bardin T (2017) 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis 76(1):29–42. https://doi.org/10.1136/annrheumdis-2016-209707 CrossRefGoogle Scholar
- 8.Cai W, Liu W, Liu C, Wang J, Zhao G (2017) A systematic review of uric acid transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia and gout and an insight into the structure-activity relationship (SAR). Chin J Struct Chem 36(6):897–910. https://doi.org/10.14102/j.cnki.02545861.2011-1596 Google Scholar
- 10.Wempe MF, Quade B, Jutabha P, Iwen T, Frick M, Rice PJ, Wakui S, Endou H (2011) Human uric acid transporter 1 (hURAT1): an inhibitor structure-activity relationship (SAR) study. Nucleosides, Nucleotides Nucleic Acids 30(12):1312–1323. https://doi.org/10.1080/15257770.2011.594031 CrossRefGoogle Scholar
- 14.Cai W, Wu J, Liu W, Xie Y, Liu Y, Zhang S, Xu W, Tang L, Wang J, Zhao G (2018) Systematic structure-activity relationship (SAR) exploration of diarylmethane backbone and discovery of a highly potent novel uric acid transporter 1 (URAT1) inhibitor. Molecules 23(2):252. https://doi.org/10.3390/molecules23020252 CrossRefGoogle Scholar
- 15.Zhang X, Wu J, Liu W, Liu Y, Xie Y, Shang Q, Zhou Z, Xu W, Tang L, Wang J, Zhao G (2017) Discovery of flexible naphthyltriazolylmethane-based thioacetic acids as highly active uric acid transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia of gout. Med Chem 13(3):260–281. https://doi.org/10.2174/1573406412666160915163002 CrossRefGoogle Scholar
- 17.Ahn SO, Ohtomo S, Kiyokawa J, Nakagawa T, Yamane M, Lee KJ, Kim KH, Kim BH, Tanaka J, Kawabe Y, Horiba N (2016) Stronger uricosuric effects of the novel selective URAT1 inhibitor UR-1102 lowered plasma urate in tufted capuchin monkeys to a greater extent than benzbromarone. J Pharmacol Exp Ther 357(1):157–166. https://doi.org/10.1124/jpet.115.231647 CrossRefGoogle Scholar
- 19.Roy K, Kar S, Das RN (2015) Understanding the basics of QSAR for applications in pharmaceutical sciences and risk assessment. Academic Press, London. https://doi.org/10.1016/B978-0-12-801505-6.00016-8 Google Scholar
- 21.Maltarollo VG, Honorio K, Emery FS, Ganesan A, Trossini GH (2015) Hologram quantitative structure-activity relationship and comparative molecular interaction field analysis of aminothiazole and thiazolesulfonamide as reversible LSD-1 inhibitors. Future Med Chem 7(11):1381–1394. https://doi.org/10.4155/fmc.15.68 CrossRefGoogle Scholar
- 29.Sato Pharmaceutical Co, Ltd. US8987473 (2015)Google Scholar
- 43.Roy K, Kar S (2014) The rm2 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 62:111–114. https://doi.org/10.1016/j.ejps.2014.05.019 CrossRefGoogle Scholar
- 49.Jiangsu Atom Bioscience and Pharmaceutical Co., Ltd. W0 2017/041732 A1Google Scholar
- 50.Fan C, Chen H, Li C (2017) Synthesis of naphthyl triazole carboxylic acid compounds and their inhibitory activities against URAT1. Drugs Clinic 32:1165–1170. https://doi.org/10.7501/j.issn.1674-5515.2017.07.001 Google Scholar