Quasi-atomistic Receptor Surrogates for the 5-HT2A Receptor: A 3D-QSAR Study on Hallucinogenic Substances

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The 5-HT2A receptor is known to act as the biological target for a series of hallucinogenic substances including substituted phenylalkylamines, tryptamines and LSD. A prerequisite for a hallucinogenic effect is an agonistic binding mode to the high-affinity state of the receptor. Attempts to establish a quantitative structure-activity relationship for such compounds are typically based on homology models or 3D-QSAR. In this paper, we describe a surrogate for the 5-HT2A receptor derived by means of quasi-atomistic receptor modeling (software Quasar), a more recently developed 3D-QSAR technique. This approach allows for the simulation of local induced fit, H-bond flip-flop, and solvation phenomena. The QSARs are established based on a family of receptor-surface models, generated by a genetic algorithm combined with cross-validation. The surrogate for the 5-HT2A receptor yielded a cross-validated q2 of 0.954 for the 23 compounds defining the training set. A series of 7 test compounds was then used to validate the model, resulting in a RMS deviation of 0.40 kcal/mol between ΔG0prd. and ΔG0exp.. The largest individual deviation was 0.61 kcal/ mol, corresponding to an uncertainty of a factor 2.7 in the binding affinity. A scramble test with negative outcome (q2=0.144, slope=−0.019) demonstrates the sensitivity of the model with respect to the biological data. Subsequently, the surrogate was used to estimate the activity of a series of 53 hypothetical congeneric compounds, some of which are predicted to be close in activity to LSD.