Predicting fragment binding modes using customized Lennard-Jones potentials in short molecular dynamics simulations.

Reliable in silico prediction of fragment binding modes remains a challenge in current drug design research. Due to their small size and generally low binding affinity, fragments can potentially interact with their target proteins in different ways. In the current study, we propose a workflow aimed at predicting favorable fragment binding sites and binding poses through multiple short molecular dynamics simulations.

Pharmacologically induced proteolysis of histone deacetylase-6 attenuates influenza virus replication despite limited anti-tumor effects.

The protein deacetylase HDAC6 has been controversially linked to cancer cell proliferation and viral propagation. We analyzed whether a pharmacological depletion of HDAC6 with a recent proteolysis-targeting chimera (PROTAC) kills tumor cells. We show that low micromolar doses of the cereblon-based PROTAC TH170, but not its inactive analog TH170E, induce proteasomal degradation of HDAC6.

Isolation of anti-inflammatory and cytotoxic secondary metabolites from Valeriana phu and evaluation of their mechanisms of action.

As a result of anti-inflammatory activity-guided fractionation, 16 secondary metabolites from the underground parts of Valeriana phu L. were obtained, including five new ones belonging to iridoid (1, 2, and 5), phenylpropanoid (6) and neolignan (7) chemical classes. Their structures were elucidated by 1D and 2D NMR analyses as well as HRESIMS.

Dona Flor and her two husbands: Discovery of novel HDAC6/AKT2 inhibitors for myeloid cancer treatment.

Unlabelled: Hematological cancer treatment with hybrid kinase/HDAC inhibitors is a novel strategy to overcome the challenge of acquired resistance to drugs. We collected IC datasets from the ChEMBL database for 13 cancer cell lines (72 h cytotoxicity, measured by MTT), known inhibitors for 38 kinases, and 10 HDACs isoforms, that we identified by target fishing and literature review. The data was subjected to rigorous biological and chemical curation leaving the final datasets ranging from 76 to 8173 compounds depending on the target.

Aromatic Amino Acid Hydroxylases as Off-Targets of Histone Deacetylase Inhibitors.

The aromatic amino acid hydroxylases (AAAHs) phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylases 1 and 2 are structurally related enzymes that contain an active site iron atom and depend on tetrahydrobiopterin (BH) as cosubstrate. Due to their important roles in synthesis of serotonin, dopamine, noradrenaline, and adrenaline and their involvement in cardiovascular, neurological, and endocrine disorders, AAAHs have been targeted by substrate analogs, iron chelators, and allosteric ligands. Phenylalanine hydroxylase is also off-target of the histone deacetylase (HDAC) inhibitor panobinostat.