ABSTRACT
Sodium butyrate [SB] is a natural cytodifferentiating and cancer preventive agent. These actions are largely triggered by inhibition of the HDAC enzyme, thereby inducing hyperacetylation/ transcription of certain genes. Unlike the prototype HDAC inhibitor, trichostatin-A [TSA], SB offers higher selectivity on cancer cells, with a lower affinity to HDAC. The mechanisms underlying these distinct biological profiles for SB remain undefined. We currently propose for, and attempt to identify differences in the binding of SB and TSA to the HDAC binding pocket. The lowest energy conformer of SB was prepositioned on TSA binding site of HDAC. Following minimization of the best-docked S8-HDAC complex, binding profiles, conformational changes and energy calculations have been derived. TSA elicited 4 hydrogen bonds with 3 key enzyme pocket residues [His131, His132 and Tyr297; bidentated]. SB missed a hydrogen bond with Tyr297 and caused more disruption of the pocket amino acid residues His131, His132 [RMS deviation value difference of up to 0.40 A]. Besides, a looser binding to the pivotal zinc atom of HDAC was evident with SB [1 vs. 2 bonds in case of TSA]. Likewise, SB was far loosely packed in the HDAC's binding tunnel as compared to TSA. Moreover, energy computations indicated that SB had a lower binding affinity than that of TSA [-27.8 vs. -66.3 Kcal/mol]. Detailed binding differences for both ligands are described. These studies demonstrate that SB binding to HDAC confers unique catalytic, conformational and computational characteristics consistent with a lower binding affinity to HDAC and a higher selectivity on cancer cells than TSA. These newly defined binding properties of SB can further state a framework strategy for the rational development of SB-like anticancer drugs with enhanced biological and safety profiles