A computational study of the resistance of HIV-1 aspartic protease to the inhibitors ABT-538 and VX-478 and design of new analogues.

Recent experimental findings with HIV-1 protease (HIV-1 PR) mutants containing variations at four residues, M46I, L63P, V82T and I84V, have shown that only mutants containing the latter two exhibit cross resistance to the inhibitors ABT-538 and VX-478. The V82T and I84V modifications in fact concern residues in the active site while the other two are in the flap (M46I) and hinge (L63P) domains of the enzyme. We have modelled the M46I/L63P, V82T/I84V and M46I/L63P/ V82T/I84V (4X) mutants of HIV-PR and computed their complexation energies with these two inhibitors. A good correlation was found between these complexation energies and the trend in published inhibition constants for these inhibitors. Reasons for the decrease in binding affinities with the two critical mutants (V82T/I84V and 4X) have also been elucidated in detail. Based on these findings, we have designed several analogues of ABT-538 and VX-478, some of which show a better calculated binding affinity towards both mutant and wild type PR.