An Approach to Rapid Estimation of Relative Binding Affinities of Enzyme Inhibitors: Application to Peptidomimetic Inhibitors of the Human Immunodeficiency Virus Type 1 Protease

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Abstract
This report describes a method for rapid assessment of the binding affinities of a series of analogous ligands to an enzyme. This approach is based on two variables (scores), representing (i) the enthalpy of binding and (ii) the strength of hydrophobic interaction. The method is then used to evaluate the binding of 11 different peptidomimetic inhibitors to the HIV-1 protease. Three-dimensional structures of these enzyme−inhibitor complexes are modeled based on the crystal structures of HIV-1 protease complexes with the known inhibitors. These structures are minimized using the AMBER force field, and the scores of binding enthalpy for each of the ligands are calculated. A second score to represent the hydrophobic interaction between a pair of atoms uses an exponential function of distance between the atoms and the product of their atomic hydrophobicity constants. This exponential function is used to assess the hydrophobic interaction energy between an enzyme and its inhibitor and also to compute and display a ‘molecular hydrophobicity map' as a 3D visualization tool. These methods are then applied to obtain trends in relative binding affinities of pairs of analogous inhibitors. Calculated scores agree well with corresponding results from thermodynamic cycle perturbation (TCP) simulations as well as experimental binding data. Since the proposed calculations are computationally cheaper and faster than TCP calculations, it is suggested that these scores can form the basis for rapid, preliminary theoretical screening of proposed derivatives of an inhibitor prior to TCP analysis, synthesis, and testing.