6 research outputs found
Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor
Orphan nuclear receptor TLX (NR2E1) plays a critical role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several critical malignancies. However, the TLX protein possesses a non-canonical ligand-binding domain (LBD), which lacks a ligand-binding pocket (conventionally targeted in case of nuclear receptors) that complicates the development of small molecule inhibitors of TLX. Herein, we utilized a rational structure-based design approach to identify small molecules targeting the Atro-box binding site of human TLX LBD. As a result of virtual screening of ~7 million molecular structures, 97 compounds were identified and evaluated in the TLX-responsive luciferase reporter assay. Among those, three chemicals demonstrated 40–50% inhibition of luciferase-detected transcriptional activity of the TLX orphan nuclear receptor at a dose of 35 µM. The identified compounds represent the first class of small molecule inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery.Other UBCReviewedFacult
Inhibitors of Tick-Borne Flavivirus Reproduction from Structure-Based Virtual Screening
Flaviviruses
form a large family of enveloped viruses affecting
millions of people over the world. To date, no specific therapy was
suggested for the infected people, making the treatment exclusively
symptomatic. Several attempts were performed earlier for the design
of fusion inhibitors for mosquito-borne flaviviruses, whereas for
the tick-borne flaviviruses such design had not been performed. We
have constructed homology models of envelope glycoproteins of tick-transmitted
flaviviruses with the detergent binding pocket in the open state.
Molecular docking of substituted 1,4-dihydropyridines and pyrido[2,1-<i>b</i>][1,3,5]thiadiazines was made against these models, and
89 hits were selected for the in vitro experimental evaluation. Seventeen
compounds showed significant inhibition against tick-borne encephalitis
virus, Powassan virus, or Omsk hemorrhagic fever virus in the 50%
plaque reduction test in PEK cells. These compounds identified through
rational design are the first ones possessing reproduction inhibition
activity against tick-borne flaviviruses