Preliminary screening of therapeutic drugs for phenylalanine hydroxylase deficiency
10.3760/cma.j.issn1008-6706.2021.11.014
- VernacularTitle:苯丙氨酸羟化酶缺乏症治疗药物初步筛选的研究
- Author:
Zhilei ZHANG
1
;
Yun SUN
;
Dingyuan MA
;
Xin WANG
;
Yanyun WANG
;
Tao JIANG
Author Information
1. 南京医科大学附属妇产医院 南京市妇幼保健院医学遗传中心 210004
- Keywords:
Phenylalanine hydroxylase deficiency;
Virtual screening;
Nefopam hydrochloride;
Fluocinonide acetate;
Risperidone;
P.D101N mutation;
Drug sensitive mutation
- From:
Chinese Journal of Primary Medicine and Pharmacy
2021;28(11):1667-1672
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To screen new drugs for treatment of phenylalanine hydroxylase deficiency.Methods:From October 2019 to October 2020, virtual drug screening was performed in Center of Genetic Medicine, Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University computer according to the characteristics of the binding ability of phenylalanine hydroxylase to drug spatial structure. Ten candidate drugs were screened from the FDA drug library (including 2 697 kinds of active pharmaceutical ingredients). A eukaryotic expression system was used to determine the effects of drugs on the activity of phenylalanine hydroxylase at the molecular level. Drug-sensitive mutants were screened.Results:Among the 10 candidate drugs, neoplasm hydrochloride, fluocinonide acetate and risperidone increased 23% [ t = 18.21, P < 0.001, vs. non-drug-treated phenylalanine hydroxylase group (i.e., only solvent and no drug added to the reaction system)], 21% ( t = 3.44, P < 0.05, vs. non-drug-treated phenylalanine hydroxylase group), 31% ( t = 19.57, P < 0.001, vs. non-drug-treated phenylalanine hydroxylase group) of the activity of phenylalanine hydroxylase. The remaining drugs exhibited weak even inhibitory effects on the activity of phenylalanine hydroxylase. 25% of p.D101N mutant could be activated by risperidone ( t = 15.86, P < 0.001, vs. non-drug-treated p.D101N mutant group). Conclusion:Neoplasm hydrochloride, fluocinonide acetate and risperidone can be used as potential therapeutic drugs for phenylalanine hydroxylase deficiency, and p.D101N mutant can be used as the drug-sensitive mutation site.
