Figure 5.
Similar ligands decompose differently into enthalpic and entropic binding contributions. Crystal structures of two closely related thrombin inhibitors bearing a cyclopentyl or cyclohexyl moiety as terminal substituent to accommodate the S3/S4 pocket of the catalytic site (surface of the binding pocket is indicated in blue). Whereas the five-membered ring (left) gives rise to a well-defined difference in electron density (white ‘chicken-wire’ contouring), the six-membered ring (right) cannot be assigned to any density (see inside white circles). It is likely that the latter fragment shows enhanced residual mobility and is scattered around several conformational states. Interestingly, this deviating behaviour is well reflected in the thermodynamic properties (centre). Both compounds exhibit the same free energy of binding (ΔG, blue columns). However, the cyclohexyl derivative (right) with the enhanced residual mobility is entropically (-TΔS, red columns) more favoured than the ‘less-well clamped’ five-ring derivative (left). The latter experiences better enthalpic contributions (ΔH, green columns) to binding [124].