Complete Characterization of the 3D Properties of the CCR5 Antagonist Vicriviroc through DFT Calculations, NMR Spectroscopy, and X-ray Analysis

Vicriviroc is a piperazine-based CCR5 receptor antagonist, with better oral availability, potency, safety, and pharmacological properties than those of its precursor SCH-C, but whose development has been stopped. A full evaluation of the 3D properties of vicriviroc was carried out in order to achieve a complete knowledge of its conformational behavior and, consequently, to identify the parameters necessary to design new, possibly better, analogs. The theoretical study was performed at the B3LYP/6-31G(d) level of calculations. Particular attention was focused on the arrangement at the planar amido function and the conformational preferences of the piperazine and piperidine rings. Several conformational families, characterized by different through-space contacts and comparable energy values, were located and confirmed by high-field NMR spectroscopy. Two distinct series of signals, originating from the barrier to rotation of the amido function, were observed in the NMR spectrum. Moreover, a NOESY experiment provided evidence for all the close contacts present assuring the coexistence, in solution, of numerous conformations in equilibrium, characterized by different chair geometries of the heterocyclic rings. A complete modeling study of vicriviroc was carried out by using theoretical calculations, and the results were confirmed through a NOESY experiment. Several populated conformations were identified originating from the amido group arrangement as well as chair inversion at the piperazine and piperidine rings and rotations around the bond connecting them.