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 and free Ligand and receptor conformations are computationally not possible for most systems of biological interest; therefore, the qualitative evaluation of a novel structure as a potential high-affinity ligand for a given receptor can benefit from taking into account both the bound and unbound (usually aqueous) low-energy geometries of the Ligand and the difference in their internal energies. Although many techniques for computationally generating and evaluating the conformational preferences of small molecules are available, there are a limited number of studies of complex organics that compare calculated and experimentally observed conformations. To assess our ability to predict a priori favored conformations of cyclic HIV protease (HIV-1 PR) inhibitors, conformational minima for nine 4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-ones I (cyclic ureas) were calculated using a high temperature quenched dynamics (QD) protocol. Single crystal X-ray and aqueous NMR structures of free cyclic ureas were obtained, and the calculated low-energy conformations compared with the experimentally observed structures. in each case the ring conformation observed experimentally is also found in the lowest energy structure of the QD analysis, although significantly different ring conformations are observed at only slightly higher energy. The 4- and 7-benzyl groups retain similar orientations in calculated and experimental structures, but torsion angles of substituents on the urea nitrogens differ in several cases. The data on experimental and calculated cyclic urea conformations and their binding affinities to HIV-1 PR are proposed as a useful dataset for assessing affinity prediction methods.