✍ Scribed by Cynthia F. Shuman; Markku D. Hämäläinen; U. Helena Danielson
No coin nor oath required. For personal study only.
Interaction kinetic and thermodynamic analyses provide information beyond that obtained in general inhibition studies, and may contribute to the design of improved inhibitors and increased understanding of molecular interactions. Thus, a biosensor-based method was used to characterize the interactions between HIV-1 protease and seven inhibitors, revealing distinguishing kinetic and thermodynamic characteristics for the inhibitors. Lopinavir had fast association and the highest affinity of the tested compounds, and the interaction kinetics were less temperature-dependent as compared with the other inhibitors. Amprenavir, indinavir and ritonavir showed non-linear temperature dependencies of the kinetics. The free energy, enthalpy and entropy (DG, DH, DS) were determined, and the energetics of complex association (DG on , DH on , DS on ) and dissociation (DG off , DH off , DS off ) were resolved. In general, the energetics for the studied inhibitors was in the same range, with the negative free energy change (DG < 0) due primarily to increased entropy (DS > 0). Thus, the driving force of the interaction was increased degrees of freedom in the system (entropy) rather than the formation of bonds between the enzyme and inhibitor (enthalpy). Although the DG on and DG off were in the same range for all inhibitors, the enthalpy and entropy terms contributed differently to association and dissociation, distinguishing these phases energetically. Dissociation was accompanied by positive enthalpy (DH off > 0) and negative entropy (DS off < 0) changes, whereas association for all inhibitors except lopinavir had positive entropy changes (DS on > 0), demonstrating unique energetic characteristics for lopinavir. This study indicates that this type of data will be useful for the characterization of target-ligand interactions and the development of new inhibitors of HIV-1 protease.
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