A. Vedani et al., Multiple-conformation and protonation-state representation in 4D-QSAR: Theneurokinin-1 receptor system, J MED CHEM, 43(23), 2000, pp. 4416-4427
Using a 4D-QSAR approach (software Quasar) allowing for multiple-conformati
on, orientation, and protonation-state ligand representation as well as for
the simulation of local induced-fit phenomena, we have validated a family
of receptor surrogates for the neurokinin-1 (NK-1) receptor system. The evo
lution was based on a population of 500 receptor models and simulated durin
g 40 000 crossover steps, corresponding to 80 generations. It yielded a cro
ss-validated r(2) of 0.887 for the 50 ligands of the training set (represen
ted by a total of 218 conformers and protomers) and a predictive r(2) of 0.
834 for the 15 ligands of the test set (70 conformers and protomers). A ser
ies of five "scramble tests" (with an average predictive r(2) of -0.438) de
monstrates the sensitivity of the surrogate toward the biological data, for
which it should establish a QSAR. On the basis of this model, the activiti
es of 12 new compounds - four of which have been synthesized and tested in
the meantime - are predicted. For most of the NK-1 antagonists, the genetic
algorithm selected a single entity - out of the up to 12 conformers or pro
tomers - to preferably bind to the receptor surrogate. Moreover, the evolut
ion converged at an identical protonation scheme for all NK-1 antagonists.
This indicates that 4D-QSAR techniques may, indeed, reduce the bias associa
ted with the choice of the bioactive conformation as each ligand molecule c
an be represented by an ensemble of conformations, orientations, and proton
ation states.