期刊
BIOORGANIC CHEMISTRY
卷 114, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.105021
关键词
Nucleotide excision repair (NER); Differential scanning fluorimetry; p8 subunit; DNA transcription; anti-cancer agents; STD-NMR
资金
- Dr. Panjwani Center for Molecular Medicine and Drug Research, (ICCBS) [3408-2019]
- Searle Company Private Ltd
The study identified 8 compounds that could potentially serve as negative modulators of p8 protein stability and have potential as anticancer agents, through biophysical screening and molecular docking experiments.
The identification of molecules, which could modulate protein-protein interactions (PPIs), is of primary interest to medicinal chemists. Using biophysical methods during the current study, we have screened 76 compounds (grouped into 16 mixtures) against the p8 subunit of the general transcription factor (TFIIH), which has recently been validated as an anti-cancer drug target. 10% of the tested compounds showed interactions with p8 protein in STD-NMR experiments. These results were further validated by molecular docking studies where interactions between compounds and important amino acid residues were identified, including Lys20 in the hydrophobic core of p8, and Asp42 and 43 in the beta 3 strand. Moreover, these compounds were able to destabilize the p8 protein by negatively shifting the Tm (>= 2 degrees C) in thermal shift assay. Thus, this study has identified 8 compounds which are likely negative modulators of p8 protein stability, and could be further considered as potential anticancer agents.
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