Identification and insights into the uncommon configuration of novel histone lysine acetyltransferase PCAF and methyltransferase GLP inhibitors from Wikstroemia chamaedaphne by molecular docking, and in vitro assessment

Biomedically important human histone acetyltransferase PCAF and histone methyltransferase GLP have emerged as interesting epigenetic targets for the development of anticancer chemotherapeutics. In this study, two novel daphnane-type diterpenes, along with ten related known ones were obtained from the flower buds of Wikstroemia chamaedaphne. Compounds 1 and 2, a ring cleavage 1α-alkyldaphnane-type backbone diterpenoids with uncommon H-10 β configuration, were elucidated by the integrated analyses of NMR spectra and experimental and calculated ECD. Compound 3 displays the most potent inhibitory activity against the histone lysine acetyltransferase PCAF and histone methyltransferase GLP. Compounds 1-3 could also bind to GLP and PCAF through hydrogen bonding, alkyl and van der Waals interactions and exhibited a high affinity as supported by the molecular docking results. In addition, molecular dynamics simulations revealed the stability of the PCAF-3 complex during the entire simulation process. Selected daphnane-type diterpenes exhibited potent activity against human BXPC-3 pancreatic cells. The cell cycle arrest experiment revealed that daphnane-type diterpenes could markedly arrest S-phases or G2/M-phase in BXPC-3 cells to inhibit cell proliferation. Overall, the results imply that daphnane-based natural products could be used as promising scaffolds for rational drug design in treatment of human diseases.