开发变构调节方法学针对几类重要疾病靶标的理论研究和应用

变构药物作为一种全新的药物作用模式，具有靶标选择性强和药物副作用低的优势。但是对于难靶靶标，目前变构药物设计还缺乏有效的方法针对这类靶标进行变构药物开发。而且，当前变构药物方法学普遍存在变构位点识别成功率低的事实，以及缺乏合理的方法研究变构药物对靶标的调控机制和变构药物作用机理。基于上述难点，在本项目中，申请人在前期对难靶K-Ras4B肿瘤蛋白和组蛋白去乙酰化酶SIRT6的研究基础上，开发隐式变构位点方法学，识别临床热点突变体K-Ras4BG12D和K-Ras4BG12V的隐式变构位点，为设计变构药物靶向难靶K-Ras4B突变体奠定基础。开发普适性的反向变构调节方法，识别SIRT6蛋白新的变构位点。阐明变构小分子对SIRT6的变构调节机制以及变构药物作用机理。这些开发的分子靶向变构药物设计的理论和方法，不仅加深对生物大分子变构调节理论的理解，也为从事创新药物研发的科研人员提供更有效的工具。

As a novel mode of drug interaction, allosteric drugs have the advantages of promising target selectivity and lower side effects. However, for some especially important yet difficult targets, there is a lack of effective methods tailored for the development of allosteric drugs. In addition, the current allosteric drug methodology faces the common challenge of low success rate in allosteric site recognition, as well as the lack of reasonable methods to study the regulatory mechanism of allosteric drugs. To tackle these difficulties, based on previous research about K-Ras4B oncoprotein, we will develop an allosteric method to identify hidden allosteric sites of the clinical hot mutants K-Ras4B G12D and K-Ras4B G12V, laying a foundation for targeting the difficult K-Ras4B mutants by allosteric modulators. Moreover, based on previous research about histone deacetylase SIRT6, we will develop a general method of reversing allosteric regulation to identify new allosteric sites on SIRT6, illustrate the allosteric regulatory mechanisms of small molecules targeting SIRT6, and reveal the pharmaceutic action mechanisms of allosteric drugs. These developed methods for molecule-targeted allosteric drug design, not only deepen the understanding of biomacromolecule allosteric regulation, but also provide more effective tools for the researchers engaged in innovative drug development.