A growing body of evidence suggests that p300 histone acetyltransferase plays important roles in cancer cell differentiation and proliferation. Here, we employed structure-based hierarchical virtual screening method to identify novel lead compounds of p300 histone acetyltransferase. From a screening library containing approximate 100 000 diverse druglike compounds, 33 compounds were chosen for experimental testing and one compound, 4-acetyl-2-methyl-N-morpholino-3,4-dihydro-2H-benzo[b][1, 4]thiazine-7-sulfonamide (17), showed as micromolar inhibitor. Based on its predicted binding pose, we investigated its binding characteristics by designing two series of structural modifications. The obtained structure-activity relationship results are consistent with the predicted binding model. We expect that the identified novel p300 histone acetyltransferase inhibitors will serve as starting points for further development of more potent and specific histone acetyltransferase inhibitors.

ObjectiveTo explore the mechanism of Taohong Siwutang in regulating the levels of inflammatory mediators， cysteine-dependent aspartate-specific protease Caspase-14， and recombinant envoplakin （EVPL） in the mouse model of psoriasis. MethodForty-eight BALB/c mice were randomized into blank， model， methotrexate tablets（3.6×10^-4 g·kg^-1）， and low-， medium-， and high-dose Taohong Siwutang groups（7.14，14.28，28.56 g·kg^-1）. The mouse model of psoriasis-like skin lesion was induced by applying 5% imiquimod cream on the back of mice， and drug intervention was carried out at the same time. The psoriasis area and severity index （PASI） was scored by photographing. Hematoxylin-eosin staining was employed to observe the pathological changes of the skin， which was evaluated based on the Baker score. The levels of interleukin （IL）-2， IL-17， IL-22， and IL-23 in the peripheral blood of mice were measured by the enzyme-linked immunosorbent assay. Immunohistochemical staining was adopted to detect the positive expression of Caspase-14 and EVPL in mouse skin lesions. Western blot and real-time polymerase chain reaction were employed to determine the protein and mRNA levels， respectively， of IL-2， IL-17， IL-22， IL-23， Caspase-14， and EVPL in mouse skin lesions. ResultCompared with the blank group， the model group showed increased PASI score and Baker score， elevated levels of IL-2， IL-17， IL-22， and IL-23 in the peripheral blood， up-regulated mRNA and protein levels of IL-2， IL-17， IL-22 and IL-23， and down-regulated mRNA and protein levels and positive expression of Caspase-14 and EVPL in skin lesions （P<0.05）. Compared with the model group， drug interventions reduced the PASI score and Baker score， lowered the levels of IL-2， IL-17， IL-22， and IL-23 in the peripheral blood， down-regulated the mRNA and protein levels of IL-2， IL-17， IL-22， and IL-23， and up-regulated the mRNA and protein levels and positive expression of Caspase-14 and EVPL in skin lesions （P<0.05）. ConclusionTaohong Siwutang demonstrates good anti-inflammatory effect and skin barrier repair function in the treatment of psoriasis. It can significantly reduce the levels of inflammatory mediators in the peripheral blood and skin lesions and promote the expression of Caspase-14 and EVPL involved in skin barrier repair in the mouse model of psoriasis.