Dataset Information

Identification of Small-Molecule Regulators of Testicular Receptor 4 via a Drug Repurposing Screening.

ABSTRACT: The testicular receptor 4 (TR4) is a nuclear receptor implicated in multiple pathological processes, including cancer development, chemotherapy, and radiotherapy resistance. However, no effective TR4 small-molecule regulator is available to date. Here, we assessed a physical-interaction-based surface plasmon resonance imaging assay for discovery of TR4 regulators. We screened 1018 FDA-approved drugs and obtained 126 drugs with K _D values below 10^-6 M. The dual-luciferase-based biological assay verified four activatory compounds and two inhibitory compounds against TR4. Among them, nilotinib exhibited the most potent inhibitor, with an EC₅₀ of 1.05 ?M, while genistein represented the most potent activator, with an EC₅₀ of 2.42 ?M. Both drugs were predicted to bind in the ligand binding pocket of TR4. The circular dichroism spectroscopic assay revealed differed conformation changes upon nilotinib or genistein binding. These results established our combined physical and biological approaches as a highly effective way to identify and develop new TR4 regulators.

SUBMITTER: Xia L

PROVIDER: S-EPMC7711931 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of Small-Molecule Regulators of Testicular Receptor 4 via a Drug Repurposing Screening.

Xia Liqun L Shen Danyang D Wang Huan H Ren Liangliang L Chen Yi Y Li Gonghui G

ACS omega 20201119 47

The testicular receptor 4 (TR4) is a nuclear receptor implicated in multiple pathological processes, including cancer development, chemotherapy, and radiotherapy resistance. However, no effective TR4 small-molecule regulator is available to date. Here, we assessed a physical-interaction-based surface plasmon resonance imaging assay for discovery of TR4 regulators. We screened 1018 FDA-approved drugs and obtained 126 drugs with K D values below 10-6 M. The dual-lucife ...[more]

PMID: 33283111

Similar Datasets

Project description:BackgroundConventional de novo drug design is costly and time consuming, making it accessible to only the best resourced research organizations. An emergent approach to new drug development is drug repurposing, in which compounds that have already gone through some level of clinical testing are examined for efficacy against diseases divergent than their original application. Repurposing of existing drugs circumvents the time and considerable cost of early stages of drug development, and can be accelerated by using software to screen existing chemical databases to identify suitable drug candidates.ResultsSmall-molecule Peptide-Influenced Drug Repurposing (SPIDR) was developed to identify small molecule drugs that target a specific receptor by exploring the conformational binding space of peptide ligands. SPIDR was tested using the potent and selective 16-amino acid peptide α-conotoxin MII ligand and the α3β2-nicotinic acetylcholine receptor (nAChR) isoform. SPIDR incorporates a genetic algorithm-based, heuristic search procedure, which was used to explore the ligand binding domain of the α3β2-nAChR isoform using a library consisting of 640,000 α-conotoxin MII peptide analogs. The peptides that exhibited the highest affinity for α3β2-nAChR were used as models for a small-molecule structure similarity search of the PubChem Compound database. SPIDR incorporates the SimSearcher utility, which generates shape distribution signatures of molecules and employs multi-level K-means clustering to insure fast database queries. SPIDR identified non-peptide drugs with estimated binding affinities nearly double that of the native α-conotoxin MII peptide.ConclusionsSPIDR has been generalized and integrated into DockoMatic v 2.1. This software contains an intuitive graphical interface for peptide mutant screening workflow and facilitates mapping, clustering, and searching of local molecular databases, making DockoMatic a valuable tool for researchers in drug design and repurposing.

Dataset Information

Identification of Small-Molecule Regulators of Testicular Receptor 4 via a Drug Repurposing Screening.

Publications

Identification of Small-Molecule Regulators of Testicular Receptor 4 via a Drug Repurposing Screening.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets