Amprenavir is one of six
protease inhibitors presently approved for clinical use in the therapeutic treatment of
AIDS. Biochemical and clinical studies have shown that, unlike other inhibitors,
Amprenavir is severely affected by the
protease mutation I50V, located in the flap region of the
enzyme.
TMC-126 is a second-generation inhibitor, chemically related to
Amprenavir, with a reported extremely low susceptibility to existing resistant mutations including I50V. In this paper, we have studied the thermodynamic and molecular origin of the response of these two inhibitors to the I50V mutation and the double active-site mutation V82F/I84V that affects all existing clinical inhibitors.
Amprenavir binds to the wild-type
HIV-1 protease with high affinity (5.0 x 10(9) M(-1) or 200 pM) in a process equally favored by enthalpic and entropic contributions. The mutations I50V and V82F/I84V lower the binding affinity of
Amprenavir by
a factor of 147 and 104, respectively.
TMC-126, on the other hand, binds to the wild-type
protease with extremely high binding affinity (2.6 x 10(11) M(-1) or 3.9 pM) in a process in which enthalpic contributions overpower entropic contributions by almost
a factor of 4. The mutations I50V and V82F/I84V lower the binding affinity of
TMC-126 by only
a factor of 16 and 11, respectively, indicating that the binding affinity of
TMC-126 to the
drug-resistant mutants is still higher than the affinity of
Amprenavir to the wild-type
protease. Analysis of the data for
TMC-126 and
KNI-764, another second-generation inhibitor, indicates that their low susceptibility to mutations is caused by their ability to compensate for the loss of interactions with the mutated target by a more favorable entropy of binding.