Hatmal Ma'mon M, Taha Mutasem O
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.
Future Med Chem. 2017 Jul;9(11):1141-1159. doi: 10.4155/fmc-2017-0061. Epub 2017 Jul 19.
Ligand-based pharmacophore modeling requires long list of inhibitors, while pharmacophores based on single ligand-receptor crystallographic structure can be too restricted or promiscuous.
This prompted us to combine simulated annealing molecular dynamics (SAMD) with ligand-receptor contacts analysis as means to construct pharmacophore model(s) from single ligand-receptor complex. Ligand-receptor contacts that survive numerous heating-cooling SAMD cycles are considered critical and are used to guide pharmacophore development.
This methodology was implemented to develop pharmacophores for acetylcholinesterase and protein kinase C-θ. The resulting models were validated by receiver-operating characteristic analysis and in vitro bioassay. Assay identified four new protein kinase C-θ inhibitors among captured hits, two of which exhibited nanomolar potencies.
The results illustrate the ability of the new method to extract valid pharmacophores from single ligand-protein complex.
基于配体的药效团建模需要一长串抑制剂，而基于单个配体-受体晶体结构的药效团可能过于受限或过于宽泛。
这促使我们将模拟退火分子动力学（SAMD）与配体-受体接触分析相结合，作为从单个配体-受体复合物构建药效团模型的方法。在多次加热-冷却SAMD循环后仍存在的配体-受体接触被认为是关键的，并用于指导药效团的开发。
该方法被用于开发乙酰胆碱酯酶和蛋白激酶C-θ的药效团。所得模型通过受体操作特征分析和体外生物测定进行验证。测定在捕获的命中物中鉴定出四种新的蛋白激酶C-θ抑制剂，其中两种表现出纳摩尔效力。
结果表明新方法能够从单个配体-蛋白质复合物中提取有效的药效团。
