Thermodynamic analysis of allosamidin binding to the human chitotriosidase

Human chitotriosidase (HCHT) is one of two active family 18 chitinases produced by humans, the other being acidic mammalian chitinase (AMCase). The enzyme is thought to be part of the innate human defense mechanism against fungal parasites. Recently, it has been shown that levels of HCHT bioactivity and protein are significantly increased in the circulation and lungs of systemic sclerosis patients and for this reason is a suggested therapeutic target. For this reason, we have undertaken a detailed thermodynamic investigation using isothermal titration calorimetry of the binding interaction of HCHT with the well-known family 18 chitinase inhibitor allosamidin. The binding is shown to be strong (Kd = 0.20 ± 0.03 μM and ΔGr° = −38.9 ± 0.4 kJ/mol) and driven by favorable changes in enthalpy (ΔHr° = −50.2 ± 1.2 kJ/mol) and solvation entropy (−TΔSsolv° = −41.8 ± 4.4 kJ/mol). It is accompanied with a large penalty in conformational entropy change (−TΔSconf° = 43.1 ± 4.2 kJ/mol).