CALCULATED AND EXPERIMENTAL LOW-ENERGY CONFORMATIONS OF CYCLIC UREA HIV PROTEASE INHIBITORS

One important factor influencing the affinity of a flexible ligand for a receptor is the internal strain energy required to attain the bound conformation. Calculation of fully equilibrated ensembles of bound an d free Ligand and receptor conformations are computationally not possi ble for most systems of biological interest; therefore, the qualitativ e evaluation of a novel structure as a potential high-affinity ligand for a given receptor can benefit from taking into account both the bou nd and unbound (usually aqueous) low-energy geometries of the Ligand a nd the difference in their internal energies. Although many techniques for computationally generating and evaluating the conformational pref erences of small molecules are available, there are a limited number o f studies of complex organics that compare calculated and experimental ly observed conformations. To assess our ability to predict a priori f avored conformations of cyclic HIV protease (HIV-1 PR) inhibitors, con formational minima for nine 4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-on es I (cyclic ureas) were calculated using a high temperature quenched dynamics (QD) protocol. Single crystal X-ray and aqueous NMR structure s of free cyclic ureas were obtained, and the calculated low-energy co nformations compared with the experimentally observed structures. in e ach case the ring conformation observed experimentally is also found i n the lowest energy structure of the QD analysis, although significant ly different ring conformations are observed at only slightly higher e nergy. The 4- and 7-benzyl groups retain similar orientations in calcu lated and experimental structures, but torsion angles of substituents on the urea nitrogens differ in several cases. The data on experimenta l and calculated cyclic urea conformations and their binding affinitie s to HIV-1 PR are proposed as a useful dataset for assessing affinity prediction methods.