Bg. Rao et al., CALCULATION OF SOLVATION AND BINDING FREE-ENERGY DIFFERENCES BETWEEN VX-478 AND ITS ANALOGS BY FREE-ENERGY PERTURBATION AND AMSOL METHODS, Journal of computer-aided molecular design, 10(1), 1996, pp. 23-30
VX-478 belongs to a novel class of HIV-1 protease inhibitors that are
based on N,N-disubstituted benzene sulfonamides. Force field parameter
s for the N,N-dialkyl benzene sulfonamide moiety have been assembled f
rom the literature and from our own ab initio calculations. These para
meters were employed to calculate solvation and binding free energy di
fferences between VX-478 and two analogs. The free energy perturbation
method has been used to determine these differences using two approac
hes. In the first approach, intergroup interaction terms only were inc
luded in the calculation of free energies (as in most reports of free
energy calculations using AMBER). In the second approach, both the int
er- and intragroup interaction terms were included. The results obtain
ed with the two approaches are in excellent agreement with each other
and are also in close agreement with the experimental results. The sol
vation free energies of N,N-dimethyl benzene sulfonamide derivatives (
truncated models of the inhibitors), calculated using continuum solvat
ion (AMSOL) methods, are found to be in qualitative agreement with the
experimental and free energy perturbation results. The binding and so
lvation free energy results are discussed in the context of structure-
based drug design to show how physicochemical properties (for example
aqueous solubilities and bioavailabilities) of these HIV-1 protease in
hibitors were improved, while maintaining their inhibitory potency.