Induced fit - The key for understanding LSD activity? A 4D-QSAR study on the 5-HT2A receptor system

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 induced-fit phenomena, we have validated a family of rece ptor surrogates for the 5-HT2A receptor system. The evolution was based on a population of 200 receptor models and simulated during 6,000 cross-over s teps, corresponding to 30 generations. It yielded a cross-validated r(2) of 0.951 for the 23 ligands of the training set and a predictive r(2) of 0.85 9 for the 7 ligands of the test set. In this simulation, all ligand molecul es were represented by four different conformers, obtained from a Monte-Car lo search in implicit aqueous solution. A series of six scramble tests (wit h an average predictive r(2) of -1.05) indicate a high sensitivity of the s urrogate family towards the biological data. The quantitative analysis of the contribution of the individual functional groups to the free energy of ligand binding, DeltaG degrees, reveals that t he key factors for strong binding-and hence activity-are the ligand desolva tion energy and the costs associated with induced fit, the adaptation of th e receptor-binding site to the ligand topology. While the ammonium function ality is essential for recognition, its contribution to DeltaG degrees is n ot favorable due to a high desolvation energy; important groups are rather methoxy and halide substituents. For most ligand molecules, the evolution d oes not select the lowest-energy conformer, contrary to previous assumption s in a corresponding 3D-QSAR study.