Journal of Medicinal Chemistry

Multiple conformation and protonation-state representation in 4D-QSAR: The neurokinin-1 receptor system

Authors: Angelo Vedani, Hans Briem, Max Dobler, Horst Dollinger and Daniel R. McMasters.
Journal: Journal of Medicinal Chemistry
Year: 2000
Issue: 43
Pages: 4416–4427

Biographics Laboratory 3R, Missionsstr. 60, 4055 Basel, Switzerland.
Department of Lead Discovery, Boehringer Ingelheim Pharma, D-55216 Ingelheim, Germany.
Laboratory for Organic Chemistry, ETH Zurich, CH-8092 Zürich, Switzerland.
Department of Medicinal Chemistry, Boehringer Ingelheim Pharma, D-55216 Ingelheim, Germany.

Using a 4D-QSAR approach (software Quasar) allowing for multiple-conformation, 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 receptor system. The evolution was based on a population of 500 receptor models and simulated during 40,000 cross-over steps, corresponding to 80 generations. It yielded a cross-validated r² of 0.887 for the 50 ligands of the training set (represented by a total of 218 conformers and protomers) and a predictive r² of 0.834 for the 15 ligands of the test set (70 conformers and protomers). A series of five "scramble tests" (with an average predictive r² of –0.438) demonstrates the sensitivity of the surrogate towards the biological data, for which it should establish a QSAR. Based on this model, the activities of twelve 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 twelve conformers or protomers — to preferably bind to the receptor surrogate. Moreover, the evolution converged at an identical protonation scheme for all NK-1 antagonists. This indicates that 4D-QSAR techniques may, indeed, reduce the bias associated with the choice of the bioactive conformation as each ligand molecule can be represented by an ensemble of conformations, orientations, and protonation states.