Nb-containing polyoxometalates (POMs) of the Wells-Dawson class inhibit HIV-I protease (HIV-1P) by a new mode based on kinetics, binding, and molecular modeling studies. Reaction of alpha1-K9Li[P2W17O61] or alpha (2)-K-10[P2W17O61] With aqueous H2O2 solutions of K7H[Nb6O19] followed by treatment with HCl and KCl and then crystallization affords the complexes alpha -K-7[P2W17(NbO2)O-61] (alpha (1)1) and alpha (2)-K-7[P2W17(NbO2)O-61] (alpha (2)1) in 63 and 86% isolated yields, respectively. Thermolysis of the crude peroxoniobium compounds (72-96 h in refluxing H2O) prior to treatment with KCl converts the peroxoniobium compounds to the corresponding polyoxometalates (POMs), alpha (1)-K-7[P2W17NbO62] (alpha (1)2) and alpha (2)-K-7[P2W17NbO62] (alpha (2)2), in moderate yields (66 and 52%, respectively). The identity and high purity of all four compounds were confirmed by P-31 NMR and W-183 NMR. The acid-induced dimerization of the oxo complexes differentiates sterically between the cap (alpha (2)) site and the belt (al) site in the Wells-Dawson structure (a22 dimerizes in high yield; a12 does not). All four POMs exhibit high activity in cell culture against HIV-1 (EC50 values of 0.17-0.83 muM), are minimally toxic (IC50 values of 50 to > 100 muM), and selectively inhibit purified HIV-1 protease (HIV-1P) (IC50 values for alpha (1)1, alpha (2)1, alpha (1)2, and alpha (2)2 of 2.0, 1.2, 1.5, and 1.8 muM, respectively). Thus, theoretical, binding, and kinetics studies of the POM/HIV-1P interaction(s) were conducted. Parameters for [P2W17NbO62](7-) were determined for the Kollman all-atom (KAA) force field in Sybyl 6.2. Charges for the POM were obtained from natural population analysis (NPA) at the HF/LANL2DZ level of theory. AutoDock 2.2 was used to explore possible binding locations for the POM with HIV-1P. These computational studies strongly suggest that the POMs function not by binding to the active site of HIV-1P, the mode of inhibition of all other HIV-IP protease inhibitors, but by binding to a cationic pocket on the "hinge" region of the flaps covering the active site (2 POMs and cationic pockets per active homodimer of HIV-1P). The kinetics and binding studies, conducted after the molecular modeling, are both in remarkable agreement with the modeling results: 2 POMs bind per HIV-1P homodimer with high affinities (K-i=1.1 +/- 0.5 and 4.1 +/- 1.8 nM in 0.1 and 1.0 M NaCl, respectively) and inhibition is noncompetitive (k(cat) but not K-m is affected by the POM concentration).