HDAC-biochem-14Of different histone deacetylase (HDAC) isozymes, HDAC8 is a highly malleable enzyme, and it exhibits the potential to accommodate structurally diverse ligands (albeit with moderate binding affinities) in its active site pocket. To probe the molecular basis of this feature, we performed the detailed thermodynamic studies for the binding of structurally similar ligands, which differed with respect to the “cap”, “linker”, and “metal-binding” regions of the Suberoylanilide Hydroxamic Acid (SAHA) pharmacophore, to HDAC8. The experimental data revealed that although the enthalpic (ΔH°) and entropic (ΔS°) changes for the binding of individual SAHA analogues to HDAC8 were substantially different, their binding free energies (ΔG°) were markedly similar, conforming to a strong enthalpy-entropy compensation effect. The enthalpy-entropy compensation effect was further observed in the temperature-dependent binding thermodynamics of all SAHA analogues to the enzyme. On the other hand, the magnitude of the proton inventory, intrinsic enthalpy, and the heat capacity changes (ΔCp°) associated with the ligand binding to HDAC8 markedly differed from one SAHA analogue to the other, and such features could only be rationalized in the light of the dynamic flexibility in the enzyme structure in conjunction with the organization of the active site resident water molecules. Arguments are presented that although the above binding thermodynamic features would facilitate identification of weak to moderately tight binding HDAC8 inhibitors (by a high throughput and/or virtual screening of the library of small molecules), they would pose major challenges in the structure-based rational design of highly potent and isozyme-selective inhibitors of HDAC8.

“Binding Thermodynamics of Structurally Similar Ligands to Histone Deacetylase 8 Sheds Light on Challenges in Rational Design of Potent and Isozyme-selective Inhibitors of the Enzyme”
Raushan K Singh Takayoshi Suzuki Tanmay Mandal Narayanaganesh Balsubramanian Manas K Haldar Dustin J. Mueller Jerrod A. Strode Gregory Cook Sanku Mallik , and D. K. Srivastava
Biochemistry – Accepted for publication
DOI: 10.1021/bi500711x