We previously combined molecular dynamics (classical or simulated annealing) with ligand–receptor contacts analysis as a means to extract valid pharmacophore model(s) from single ligand–receptor complexes. However, molecular dynamics methods are computationally expensive and time-consuming. Here we describe a novel method for extracting valid pharmacophore model(s) from a single crystallographic structure within a reasonable time scale. The new method is based on ligand–receptor contacts analysis following energy relaxation of a predetermined set of randomly deformed complexes generated from the targeted crystallographic structure. Ligand–receptor contacts maintained across many deformed/relaxed structures are assumed to be critical and used to guide pharmacophore development. This methodology was implemented to develop valid pharmacophore models for PI3K-γ, RENIN, and JAK1. The resulting pharmacophore models were validated by receiver operating characteristic (ROC) analysis against inhibitors extracted from the CHEMBL database. Additionally, we implemented pharmacophores extracted from PI3K-γ to search for new inhibitors from the National Cancer Institute list of compounds. The process culminated in new PI3K-γ/mTOR inhibitory leads of low micromolar IC₅₀s.

中文翻译：

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结合随机变形/松弛和分子间接触分析从配体-受体复合物中提取药效基团

我们以前将分子动力学（经典或模拟退火）与配体-受体接触分析相结合，以此作为从单个配体-受体复合物中提取有效药效团模型的方法。然而，分子动力学方法在计算上是昂贵且费时的。在这里，我们描述了一种在合理的时间范围内从单个晶体学结构中提取有效药效团模型的新颖方法。该新方法基于配体-受体接触分析，该分析是根据目标晶体结构产生的一组预定随机变形的复合物的能量弛豫后进行的。跨许多变形/松弛结构维持的配体-受体接触被认为是至关重要的，并用于指导药效团的发展。实施此方法可为PI3K-γ，RENIN和JAK1开发有效的药效团模型。通过针对从CHEMBL数据库提取的抑制剂的接收者操作特征（ROC）分析验证了所得的药效团模型。此外，我们实施了从PI3K-γ提取的药效基团，以从美国国家癌症研究所的化合物列表中寻找新的抑制剂。该工艺最终产生了低微摩尔IC的新型PI3K-γ/ mTOR抑制性引线₅₀秒