Computational characteristics of valproic acid binding to histone deacetylase

Recently, the antiepileptic drug valproic acid [VPA] has also demonstrated efficacy in the management of cancer and bipolar disorders. These actions are largely mediated by inhibition of the HDAC enzyme/induction of certain genes. Relative to other HDAC inhibitors such as trichostatin-A [TSA], VPA offers higher selectivity on cancer cells with virtually no detrimental effects on normal cells. The molecular underpinnings of these biological profiles for VPA remain undefined. We currently propose for and attempt to identify differences in the binding of VPA and TSA to HDAC. In this paper, conformational changes and energy calculations have been derived. VPA had to accomplish conformational changes in its structure for best accommodation at the HDAC binding site. Energy computations showed that VPA has a lower binding affinity than TSA [-53.80 vs. -66.30 Kcal/mol]. These findings demonstrate that VPA binding to HDAC confers catalytic, conformational, and computational characteristics that are distinct from those of TSA. These findings for VPA are consistent with a moderate inhibition of HDAC, a low toxicity on normal cells, and a higher selectivity on cancer cells than TSA. Accordingly, these newly identified binding properties of VPA can state a framework strategy for the rational design of VPA-related anticancer drugs with superior cytodifferentiating- and/or safety-profiles

Heterogeneity of the mechanisms underlying activation of adenylatecyclase by endothelin-1 in rabbit and bovine iris sphincter and tracheal smooth muscles

In the bovine and rabbit iris sphincters and tracheas, endothelin-l [ET -1] activated adenylate cyclase [AC] in a concentration-dependent manner. The rate of cAMP formation decreased in the order, bovine iris sphincter > rabbit trachea > > rabbit iris sphincter > > bovine trachea. Maximal values for AC activation in bovine iris sphincter and rabbit trachea were 398% and 392% of basal activity respectively. Pretreatment with indomethacin [1 [micro]M], a cyclooxygenase inhibitor, virtually abolished the increase by ET-1 of cAMP levels in rabbit trachea and bovine trachea [96% reduction]. In the rabbit iris sphincter, indomethacin and nordihydroguairetic acid [NDGA] [1 [micro] M] lipoxygenase inhibitor, brought about 60 and 28% reduction of ET -1 response, respectively. Co-treatment with both eicosanoid inhibitors [1 [micro] M, each] eliminated the ET-1-evoked cAMP formation. Quinacrine [50 [micro] M], a phospholipase A2 [PLA2] inhibitor, attenuated cAMP production by ET -1 at a less prominent rate than that of indomethacin [38 to 70% reduction in cAMP increments]. At odds, in the bovine iris sphincter, the cAMP response was unaltered by all prostanoid inhibitors. Moreover, challenge with nicardipine [-a] Ca [2+] channel blocker, trifluoperazine -a calmodulin inhibitor, or staurosporine -a PKC inhibitor, had no significant effect on the responsiveness to ET -1, suggesting lack of mediators in the coupling of ET - receptors to AC system, in the bovine iris sphincter. In conclusion, activation of AC by ET -1 may represent a widespread phenomenon in smooth muscles. The mechanism whereby ET -1 elicits cAMP production is diverse and may include eicosanoids both from cyclooxygenase and lipoxygenase origins as mediators