Discovery of potential xanthine oxidase inhibitors based on virtual screening

doi:10.5246/jcps.2023.08.052

Abstract

Abstract:

With the continuous improvement of living standards, the incidence of gout is increasing rapidly, and it is becoming more common among younger individuals. Xanthine oxidase (XO) is a crucial target for treating gout, as inhibiting XO can effectively reduce the production of uric acid in the body and alleviate gout symptoms. In the present study, three potential XO inhibitors were identified through virtual screening and validated using surface plasmon resonance (SPR). Among these inhibitors, floxuridine exhibited the strongest binding activity at 0.35 μM, compared with 0.76 μM for the positive drug allopurinol. Molecular dynamics simulations were conducted to examine the binding pattern of these compounds with XO. It is noteworthy that all three compounds are already approved as marketed drugs and have established safety profiles, indicating their potential as effective XO inhibitors.

Key words: Virtual screening, Xanthine oxidase inhibitors, Surface plasmon resonance, Drug discovery

Supporting: /attached/file/20230903/20230903000355_184.pdf

Xiaowei Chi, Qi Li, Yi Zhong, Tong Gong, Chuxiao Yi, Liangren Zhang, Zhenming Liu. Discovery of potential xanthine oxidase inhibitors based on virtual screening[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(8): 626-635.

Figures/Tables 5

References 22

[1]	Dalbeth, N.; Gosling, A.L.; Gaffo, A.; Abhishek, A. Gout. Lancet. 2021, 397, 1843–1855.
[2]	Chen-Xu, M.; Yokose, C.; Rai, S.K.; Pillinger, M.H.; Choi, H.K. Contemporary prevalence of gout and hyperuricemia in the United States and decadal trends: the national health and nutrition examination survey, 2007-2016. Arthritis Rheumatol. 2019, 71, 991–999.
[3]	Dalbeth, N.; House, M.E.; Horne, A.; Karu, L.; Petrie, K.J.; McQueen, F.M.; Taylor, W.J. The experience and impact of gout in Māori and Pacific people: a prospective observational study. Clin. Rheumatol. 2013, 32, 247–251.
[4]	Dalbeth, N.; Dowell, T.; Gerard, C.; Gow, P.; Jackson, G.; Shuker, C.; Te Karu, L. Gout in Aotearoa New Zealand: the equity crisis continues in plain sight. N. Z. Med. J. 2018, 131, 8–12.
[5]	Dehlin, M.; Drivelegka, P.; Sigurdardottir, V.; Svärd, A.; Jacobsson, L.T.H. Incidence and prevalence of gout in Western Sweden. Arthritis Res. Ther. 2016, 18, 1–7.
[6]	Kuo, C.F.; Grainge, M.J.; Mallen, C.; Zhang, W.Y.; Doherty, M. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Ann. Rheum. Dis. 2015, 74, 661–667.
[7]	Dubreuil, M.; Neogi, T.; Chen, C.A.; Choi, H.K.; Chaisson, C.E.; Hunter, D.J.; Zhang, Y.Q. Increased risk of recurrent gout attacks with hospitalization. Am. J. Med. 2013, 126, 1138–1141.e1.
[8]	Rothenbacher, D.; Primatesta, P.; Ferreira, A.; Cea-Soriano, L.; Rodríguez, L.A.G. Frequency and risk factors of gout flares in a large population-based cohort of incident gout. Rheumatology. (Oxford). 2011, 50, 973–981.
[9]	Taylor, W.J.; Fransen, J.; Jansen, T.L.; Dalbeth, N.; Schumacher, H.R.; Brown, M.; Louthrenoo, W.; Vazquez-Mellado, J.; Eliseev, M.; McCarthy, G.; Stamp, L.K.; Perez-Ruiz, F.; Sivera, F.; Ea, H.K.; Gerritsen, M.; Scire, C.; Cavagna, L.; Lin, C.; Chou, Y.Y.; Tausche, A.K.; Vargas-Santos, A.B.; Janssen, M.; Chen, J.H.; Slot, O.; Cimmino, M.A.; Uhlig, T.; Neogi, T. Study for updated gout classification criteria: identification of features to classify gout. Arthritis Care Res. 2015, 67, 1304–1315.
[10]	Singh, J.A.; Herbey, I.; Bharat, A.; Dinnella, J.E.; Pullman-Mooar, S.; Eisen, S.; Ivankova, N. Gout self-management in African American veterans: a qualitative exploration of challenges and solutions from patients’ perspectives. Arthritis Care Res. 2017, 69, 1724–1732.
[11]	Kumar, R.; Joshi, G.; Kler, H.; Kalra, S.; Kaur, M.; Arya, R. Toward an understanding of structural insights of xanthine and aldehyde oxidases: an overview of their inhibitors and role in various diseases. Med. Res. Rev. 2018, 38, 1073–1125.
[12]	Gao, J.; Zhang, Z.F.; Zhang, B.; Mao, Q.; Dai, X.W.; Zou, Q.; Lei, Y.; Feng, Y.; Wang, S.J. Novel 3-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-1,2,4-oxadiazol-5(4H)-ones as promising xanthine oxidase inhibitors: design, synthesis and biological evaluation. Bioorg. Chem. 2020, 95, 103564.
[13]	Gliozzi, M.; Malara, N.; Muscoli, S.; Mollace, V. The treatment of hyperuricemia. Int. J. Cardiol. 2016, 213, 23–27.
[14]	Burmaoglu, S.; Ozcan, S.; Balcioglu, S.; Gencel, M.; Ali Noma, S.A.; Essiz, S.; Ates, B.; Algul, O. Synthesis, biological evaluation and molecular docking studies of bis-chalcone derivatives as xanthine oxidase inhibitors and anticancer agents. Bioorg. Chem. 2019, 91, 103149.
[15]	Singh, J.A.; Akhras, K.S.; Shiozawa, A. Comparative effectiveness of urate lowering with febuxostat versus allopurinol in gout: analyses from large U.S. managed care cohort. Arthritis Res. Ther. 2015, 17, 120.
[16]	Hammer, B.; Link, A.; Wagner, A.; Bohm, M. Fatal allopurinol-induced hypersensitivity syndrome in asymptomatic hyperuricaemia. Deut Med. Wochenschr. 2001, 126, 1331–1334.
[17]	Šmelcerović, A.; Tomović, K.; Šmelcerović, Ž.; Petronijević, Ž.; Kocić, G.; Tomašič, T.; Jakopin, Ž.; Anderluh, M. Xanthine oxidase inhibitors beyond allopurinol and febuxostat; an overview and selection of potential leads based on in silico calculated physico-chemical properties, predicted pharmacokinetics and toxicity. Eur. J. Med. Chem. 2017, 135, 491–516.
[18]	Gao, J.; Liu, X.G.; Zhang, B.; Mao, Q.; Zhang, Z.; Zou, Q.; Dai, X.W.; Wang, S.J. Design, synthesis and biological evaluation of 1-alkyl-5/6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbonitriles as novel xanthine oxidase inhibitors. Eur. J. Med. Chem. 2020, 190, 112077.
[19]	Okamoto, K.; Eger, B.T.; Nishino, T.; Kondo, S.; Pai, E.F.; Nishino, T. An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J. Biol. Chem. 2003, 278, 1848–1855.
[20]	Matsumoto, K.; Okamoto, K.; Ashizawa, N.; Nishino, T. FYX-051: a novel and potent hybrid-type inhibitor of xanthine oxidoreductase. J. Pharmacol. Exp. Ther. 2011, 336, 95–103.
[21]	Hosoya, T.; Sasaki, T.; Hashimoto, H.; Sakamoto, R.; Ohashi, T. Clinical efficacy and safety of topiroxostat in Japanese male hyperuricemic patients with or without gout: an exploratory, phase 2a, multicentre, randomized, double-blind, placebo-controlled study. J. Clin. Pharm. Ther. 2016, 41, 298–305.
[22]	Robinson, P.C.; Dalbeth, N. Febuxostat for the treatment of hyperuricaemia in gout. Expert Opin. Pharmacother. 2018, 19, 1289–1299.