Structure-guided discovery of high affinity TAS2R14 ligands

TAS2Rs是介导苦味识别的G蛋白偶联受体（gpcr）。越来越多的证据表明，这些化学感觉受体也在口外组织中表达。特别是，TAS2R14亚型在人类气道平滑肌中被发现，可能是气道疾病的新药物靶点。开发高亲和力的TAS2R14受体激动剂和拮抗剂将有助于开展TAS2R14的生物学、生理学和结构研究，并可能对药物发现产生重大影响。该项目旨在利用德国Peter Gmeiner教授的实验室与以色列Masha Niv教授的实验室之间的密切合作来开发此类化合物，前者在GPCR配体的发现方面具有长期经验，后者在计算方法方面具有强大的专业知识，特别是在苦味受体和配体方面。高亲和力TAS2R14配体的设计和合成将通过基于文库的体外筛选、大型硅文库对接和hit-to-lead优化相结合的方法来完成。我们将利用我们的筛选结果来完善TAS2R14的结构模型，用于数百万个具有广泛化学空间的分子文库的计算对接筛选。在基于细胞的G蛋白激活和β -抑制蛋白募集试验中，对hit进行详细的药理学评估，将为TAS2R家族的信号传导提供新的见解，特别是考虑到目前对gpcr的偏性激动作用的认识。Hit-to-lead优化和进一步的结构修饰将获得高亲和力的TAS2R14配体、特定的放射性配体和共价配体，这些配体可能有助于构建稳定的受体-配体复合物。新开发的TAS2R14配体将在药物开发、食品科学和结构生物学等领域引起广泛关注。

TAS2Rs are G protein-coupled receptors (GPCRs) that mediate bitter taste recognition. There is accumulating evidence that these chemosensory receptors are also expressed in extraoral tissues. In particular, the subtype TAS2R14 was found in human airway smooth muscle and may be a novel drug target for airway diseases. A detailed understanding of bitter taste receptor biology as well as structural information on these receptors are still lacking The development of high affinity agonists and antagonists for TAS2R14 will enable biological, physiological and structural studies and may also have a significant impact on drug discovery. This project aims to develop such compounds by taking advantage of an intensive collaboration between the lab of Professor Peter Gmeiner in Germany with a long-standing experience in the discovery of GPCR ligands, and the lab of Professor Masha Niv in Israel, with strong expertise in computational approaches, in particular for bitter taste receptors and ligands. The design and synthesis of high affinity TAS2R14 ligands will be performed by a combination of approaches integrating library-based in vitro screening, docking of large in silico libraries and hit-to-lead optimization. We will use our screening hits to refine structural models of TAS2R14 for computational docking screens of multi-million molecule libraries with wide chemical space. A detailed pharmacological evaluation of hits in cell-based assays for G protein activation and beta-arrestin recruitment will provide novel insights into the signaling of the TAS2R family, particularly in view of the current appreciation of biased agonism in GPCRs. Hit-to-lead optimization and further structural modifications will give access to high affinity TAS2R14 ligands, a specific radioligand and covalent ligands that may be useful for the construction of stable receptor-ligand complexes. The newly developed TAS2R14 ligands will be of great interest for drug discovery, food science and structural biology.