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

Meike Schulze-Alexandru, K. Kovar, A. Vedani
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引用次数: 8

Abstract

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 q 2 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 kcalymol between DG 0 prd. and DG 0 exp.. The largest individual deviation was 0.61 kcaly mol, corresponding to an uncertainty of a factor 2.7 in the binding affinity. A scramble test with negative outcome (q 2 a 0.144, slopea 7 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.
5 - HT2A受体的准原子受体替代品:致幻物质的3D - QSAR研究
已知5-HT2A受体是一系列致幻物质的生物靶点,包括取代苯烷基胺、色胺和LSD。致幻作用的先决条件是受体的高亲和力状态的激动结合模式。试图建立这类化合物的定量构效关系通常是基于同源性模型或3D-QSAR。在本文中,我们描述了通过准原子受体建模(Quasar软件)获得的5-HT2A受体的替代品,这是最近开发的3D-QSAR技术。这种方法允许模拟局部诱导拟合,氢键触发器和溶剂化现象。qsar是基于一系列受体表面模型建立的,由遗传算法和交叉验证相结合产生。对于定义训练集的23种化合物,5-HT2A受体替代物的交叉验证q 2为0.954。然后使用一系列7个测试化合物来验证模型,结果在DG 0 prd之间的RMS偏差为0.40 kcalymol。和DG 0 exp..最大个体偏差为0.61 kcalmol,对应于2.7因子的结合亲和力的不确定性。一个阴性结果的混乱测试(q2 A 0.144,斜率7 0.019)证明了该模型相对于生物学数据的敏感性。随后,该替代物被用来估计一系列53种假设的同类化合物的活性,其中一些被预测在活性上接近LSD。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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