Theoretical Studies on the Inhibitory Activity of Levofloxacin-thiadiazole HDACi Conjugates to Histone Deacetylases

摘要

Electrotopological state indices (E_K) of atom types is used to describe the structures of 19 conjugates (LHCc) of levofloxacin-thiadiazole HDAC inhibitor (HDACi) and related to the inhibitory activity (pW_i, i=1, 6) of LHCc against histone deacetylases (HDACs, HDAC1 and HDAC6). The optimal two-parameter (E_(17), E_(18)) quantitative structure-activity relationships(QSAR) models are established by using leaps-and-bounds regression analysis for the inhibitory activities (pW_i) of 19 above compounds to HDAC1 and HDAC6 along with the E_K. The correlation coefficients (R~2) and the leave-one-out (LOO) cross validation R_(cv)~2 for the pW_1 and pW_6 models were 0.942 and 0.918, 0.943 and 0.919, respectively. The QSAR models have favorable correlation, as well as robustness and good prediction capability by R~2, F, R_(cv)~2, A_(IC), F_(IT), V_(IF) tests. The results indicate that the molecular structural units: -NH_2, -NH- are main factors which can affect the inhibitory activity(pW_i)bioactivities of these compounds directly. Accordingly, it is suggested that the main interactions between HDACs inhibitor and HDACs are hydrophobic, hydrogen bond, and coordination compounds with Zn~(2+). This is consistent with the molecular docking results of document.