哮喘是目前无法通过药物彻底治愈的常见慢性疾病且呈快速上升趋势。肌动蛋白结合蛋白-2（TG2）及化合物TSG12是最新发现的新型抗哮喘靶标蛋白及其激动剂，但该蛋白激动构象未知、无典型配体结合空腔、与其激动剂结合机制不清，难以用常规药物设计策略对激动剂进行优化。本项目拟以新发展的高效分子动力学构象采样方法对其全长结构进行系统的模拟和构象采样，预测一系列可药性构象，在此基础上开展两方面工作。一是预测并实验确认激动剂结合位点，并据此设计TSG12的新颖类似物，克服其固有的化学和代谢稳定性差等缺点。另一方面是基于预测的一系列靶标可药性构象，开展药物发现与优化研究，获得结合作用机制及骨架结构不同于TSG12的新型TG2激动剂。项目在药物设计策略、靶标蛋白结合位点及化合物结构等方面具有显著的创新性，并可为哮喘的临床治疗提供基于新靶标新机制TG2激动剂药物先导化合物，科研价值与社会效益明显。

Asthma is a common chronic disease without permanently remediable drug, which is increasing rapidly. A protein, namely transgelin-2 (TG2), and a compound, namely TSG12, are the newly identified novel drug target for asthma and the agonist of TG2. However, the agonist-binding conformation, agonist-binding site and agonist-binding mechanism of the target protein are unknown, leading to a great challenge to computer-aided drug design for the structural optimization of the agonist TSG12. This proposal will focus on two issues by starting from systematic modelling and sampling of druggable conformations of TG2 with our newly developed high-performance molecular dynamics simulation methods. The first issue is the prediction and validation of the binding mechanism between TG2 and TSG12, which is helpful for structural optimization to overcome the inherent weakness of chemical and metabolic instability of TSG12. The second issue is to discover and optimize novel TG2 agonists with novel molecular structure and binding mechanism different from TSG12 through drug discovery and optimization approaches based on the predicted druggable conformations. This proposed project not only has obvious novity of research of molecular modeling and design strategy, binding site and molecular structure of new TG2 agonist, but also provide various TG2 agonists as drug leads against asthma based on novel target and binding mechanism. In overall, this project has impressive significance of scientific research and social benefits.