In Silico Drug Repurposing by Structural Alteration after Induced Fit: Discovery of a Candidate Agent for Recovery of Nucleotide Excision Repair in Xeroderma Pigmentosum Group D Mutant (R683W)

Biomedicines

Eiji Nakano¹  Chikako Nishigori¹  Takashi Suzuki²  Mika Ohta²  Aki Sugano²  Yutaka Takaoka²  Kenji Miura²  Satoshi Tateishi³ 

[1] Division of Dermatology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;Division of Medical Informatics and Bioinformatics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan;

关键词: drug repurposing;    induced fit;    molecular dynamics simulation;    xeroderma pigmentosum complementation group D;    ATP binding;    4E1RCat;   

DOI  :  10.3390/biomedicines9030249

来源: DOAJ

【 摘 要 】

Xeroderma pigmentosum complementation group D (XPD) is a UV-sensitive syndrome and a rare incurable genetic disease which is caused by the genetic mutation of the excision repair cross-complementation group 2 gene (ERCC2). Patients who harbor only XPD R683W mutant protein develop severe photosensitivity and progressive neurological symptoms. Cultured cells derived from patients with XPD (XPD R683W cells) demonstrate a reduced nucleotide excision repair (NER) ability. We hope to ameliorate clinical symptoms if we can identify candidate agents that would aid recovery of the cells’ NER ability. To investigate such candidates, we created in silico methods of drug repurposing (in silico DR), a strategy that utilizes the recovery of ATP-binding in the XPD R683W protein after the induced fit. We chose 4E1RCat and aprepitant as the candidates for our in silico DR, and evaluated them by using the UV-induced unscheduled DNA synthesis (UDS) assay to verify the recovery of NER in XPD R683W cells. UDS values of the cells improved about 1.4–1.7 times after 4E1RCat treatment compared with solvent-only controls; aprepitant showed no positive effect. In this study, therefore, we succeeded in finding the candidate agent 4E1RCat for XPD R683W. We also demonstrated that our in silico DR method is a cost-effective approach for drug candidate discovery.

【 授权许可】

Unknown