Data from: Towards high-resolution modeling of small molecule - ion channel interactions

Ion channels are critical drug targets for a range of pathologies, such as
epilepsy, pain, itch, autoimmunity, and cardiac arrhythmias. To develop
effective and safe therapeutics, it is necessary to design small molecules
with high potency and selectivity for specific ion channel subtypes. There
has been increasing implementation of structure-guided drug design for the
development of small molecules targeting ion channels. We evaluated the
performance of two Rosetta ligand docking methods, RosettaLigand and
GALigandDock, on structures of known ligand - cation channel complexes.
Ligands were docked to voltage-gated sodium (NaV), voltage-gated calcium
(CaV), and transient receptor potential vanilloid (TRPV) channel families.
For each test case, RosettaLigand and GALigandDock methods were able to
frequently sample a ligand binding pose within 1-2 Å root mean square
deviation (RMSD) relative to the experimental ligand coordinates. However,
RosettaLigand and GALigandDock scoring functions cannot consistently
identify experimental ligand coordinates as top-scoring models. Our study
reveals that the proper scoring criteria for RosettaLigand and
GALigandDock modeling of ligand - ion channel complexes should be assessed
on a case-by-case basis using sufficient ligand and receptor interface
sampling, knowledge about state specific interactions of the ion channel
and inherent receptor site flexibility that could influence ligand
binding.

离子通道是多种病理状况的关键药物靶点，例如癫痫、疼痛、瘙痒、自身免疫病和心律失常。为开发有效且安全的治疗药物，需设计对特定离子通道亚型具有高效价和选择性的小分子。在针对离子通道的小分子开发中，结构引导药物设计的应用日益增多。我们评估了两种Rosetta配体对接方法（RosettaLigand和GALigandDock）在已知配体-阳离子通道复合物结构上的性能。配体被对接至电压门控钠通道（NaV）、电压门控钙通道（CaV）和瞬时受体电位香草酸亚型（TRPV）通道家族。在每个测试案例中，RosettaLigand和GALigandDock方法能够频繁采样到与实验配体坐标的均方根偏差（RMSD）在1-2埃范围内的配体结合构象。然而，RosettaLigand和GALigandDock的评分函数无法持续将实验配体坐标识别为最高评分模型。我们的研究表明，针对配体-离子通道复合物的RosettaLigand和GALigandDock建模，其合适的评分标准应通过充分的配体与受体界面采样、离子通道状态特异性相互作用的知识以及可能影响配体结合的受体位点固有柔性，进行个案评估。