(Chief Bee)
01-16-03 06:41
No 398698
(Rated as: excellent)
Quasi-atomistic receptor surrogates for the 5-HT2A receptor: a 3D-QSAR study on hallucinogenic substances.
Schulze-Alexandru, Meike; Kovar, Karl-Artur; Vedani, Angelo.
Abstract
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) (../rhodium/pdf /quasi-atomis
(Newbee)
01-16-03 16:11
No 398869
good article, thanks!
get upa, geero up!