HIV-1 IN is an essential enzyme for
viral replication and an interesting target for the
design of new pharmaceuticals for use in multidrug
therapy of AIDS. L-731,988 is one of the most active
molecules of the class of -diketo acids. Individual
and combined mutations of HIV-1 IN at residues
T66, S153, and M154 confer important degrees of
resistance to one or more inhibitors belonging to
this class. In an effort to understand the molecular
mechanism of the resistance of T66I/M154I IN to the
inhibitor L-731,988 and its specific binding modes,
we have carried out docking studies, explicit solventMDsimulations,
and binding free energy calculations.
The inhibitor was docked against different
protein conformations chosen from priorMDtrajectories,
resulting in 2 major orientations within the
active site. MD simulations have been carried out
for the T66I/M154I DM IN, DM IN in complex with
L-731,988 in 2 different orientations, and 1QS4 IN in
complex with L-731,988. The results of these simulations
show a similar dynamical behavior between
T66I/M154I IN alone and in complex with L-731,988,
while significant differences are observed in the
mobility of the IN catalytic loop (residues 138–149).
Water molecules bridging the inhibitor to residues
from the active site have been identified, and residue
Gln62 has been found to play an important role
in the interactions between the inhibitor and the
protein. This work provides information about the
binding modes of L-731,988, as well as insight into
the mechanism of inhibitor–resistance in HIV-1 integrase.
