AN APPROACH TO RAPID ESTIMATION OF RELATIVE BINDING AFFINITIES OF ENZYME-INHIBITORS - APPLICATION TO PEPTIDOMIMETIC INHIBITORS OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE

This report describes a method for rapid assessment of the binding aff inities of a series of analogous ligands to an enzyme. This approach i s based on two variables (scores), representing (i) the enthalpy of bi nding and (ii) the strength of hydrophobic interaction. The method is then used to evaluate the binding of 11 different peptidomimetic inhib itors to the HIV-1 protease. Three-dimensional structures of these enz yme-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 e nthalpy for each of the ligands are calculated. A second score to repr esent the hydrophobic interaction between a pair of atoms uses an expo nential function of distance between the atoms and the product of thei r atomic hydrophobicity constants. This exponential function is used t o 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 obt ain trends in relative binding affinities of pairs of analogous inhibi tors. Calculated scores agree well with corresponding results from the rmodynamic cycle perturbation (TCP) simulations as well as experimenta l binding data. Since the proposed calculations are computationally ch eaper and faster than TCP calculations, it is suggested that these sco res can farm the basis for rapid, preliminary theoretical screening of proposed derivatives of an inhibitor prior to TCP analysis, synthesis , and testing.