Tautomerism and magnesium chelation of HIV-1 integrase inhibitors: a theoretical study.

The tautomerism and corresponding transition states of four authentic HIV-1 integrase (IN) inhibitor prototype structures, alpha,gamma-diketo acid, alpha,gamma-diketotriazole, dihydroxypyrimidine carboxamide and 4-quinolone-3-carboxylic acid, were investigated at the B3LYP/6-311++G(d,p) level in vacuum and in aqueous solvent models. To study the possible chelating modes of these tautomers with two magnesium ions--a process important for inhibition--we modeled an assembly of three formic acids, four water molecules and two Mg(2+) ions as a template mimicking the binding site of IN. The DFT calculation results show that deprotonated enolized or phenolic hydroxy groups of specific tautomers in water lead to the most stable complexes, with the two magnesium ions separated by a distance of approximately 3.70 to 3.74 A, and with each magnesium ion at the center of an octahedron. The drug candidate GS-9137 (Gilead), based on the 4-quinolone-3-carboxylic acid scaffold, and its analogues form similar but different chelating modes. When one water molecule in the complex is replaced by a methanol molecule, which mimics the terminal 3'-OH of viral DNA, a good chelating complex is retained. This supports the hypothesis that, in the binding site of IN after 3'-processing, the terminal 3'-OH of viral DNA interacts with one Mg(2+) by chelation.