Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences , The Hashemite University , P.O. Box 330127 , Zarqa 13133 , Jordan.
Drug Discovery Unit, Department of Pharmaceutical Sciences, Faculty of Pharmacy , University of Jordan , Amman 11942 , Jordan.
J Chem Inf Model. 2018 Apr 23;58(4):879-893. doi: 10.1021/acs.jcim.7b00708. Epub 2018 Mar 19.
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 ICs.
我们之前将分子动力学（经典或模拟退火）与配体-受体接触分析相结合，作为从单个配体-受体复合物中提取有效药效团模型的一种方法。然而，分子动力学方法计算成本高且耗时。在这里，我们描述了一种在合理的时间范围内从单个晶体结构中提取有效药效团模型的新方法。该新方法基于配体-受体接触分析，在从目标晶体结构生成的预定随机变形复合物的能量弛豫之后进行。假定在许多变形/弛豫结构中保持的配体-受体接触是关键的，并用于指导药效团的开发。该方法学用于为 PI3K-γ、RENIN 和 JAK1 开发有效的药效团模型。通过针对 CHEMBL 数据库中提取的抑制剂对所得药效团模型进行接收者操作特性 (ROC) 分析来验证其有效性。此外，我们还实施了从 PI3K-γ 中提取的药效团，以从国家癌症研究所的化合物列表中搜索新的抑制剂。该过程最终得到了具有低微摩尔 IC50 的新的 PI3K-γ/mTOR 抑制先导化合物。
