Author Topic: 3D-QSAR study on hallucinogenic substances  (Read 2860 times)

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3D-QSAR study on hallucinogenic substances
« on: January 16, 2003, 06:41:00 AM »
Quasi-atomistic receptor surrogates for the 5-HT2A receptor: a 3D-QSAR study on hallucinogenic substances.
Schulze-Alexandru, Meike; Kovar, Karl-Artur; Vedani, Angelo.


The 5-HT2A receptor is known to act as the biol. 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 quant. structure-activity relationship for such compds. are typically based on homol. 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 compds. defining the training set.  A series of 7 test compds. was then used to validate the model, resulting in a RMS deviation of 0.40 kcal/mol between DGprd0 and DGexp.0.  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 neg. outcome (q2=0.144, slope= -0.019) demonstrates the sensitivity of the model with respect to the biol. data.  Subsequently, the surrogate was used to est. the activity of a series of 53 hypothetical congeneric compds., some of which are predicted to be close in activity to LSD.

Quantitative Structure-Activity Relationships 18(6), 548-560 (1999)



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good article, thanks!
« Reply #1 on: January 16, 2003, 04:11:00 PM »
good article, thanks!