Targeting the MSH2-dependent Apoptotic Pathway

描述（由申请人提供）：计算建模、细胞生物学、生物物理学、化学实验和动物模型将结合在一种新的方法中，用于药物设计的化合物预筛选，这种方法比目前的方法更有效、更快速。这项跨学科的研究整合了：(i)结合蛋白质动力学的计算建模，以筛选有利于特定蛋白质构象的化合物，并以最佳方式诱导细胞死亡，然后进行细化以预测更有效的化合物；（ii）最有前途的化合物的化学合成；（iii）细胞生物学实验以验证预测，帮助改进计算预测并进行临床前评估；然后（iv）筛选体内最有希望的化合物。我们的目标是一种特定的蛋白，MMR蛋白MSH2 (MutS同源物2)，因为我们已经证明，这种蛋白在DNA损伤（特别是铂损伤）的反应中会发生特定的构象变化，最终导致细胞死亡。我们正在专门设计能够诱导MSH2中相同构象变化并最终引发细胞死亡的化合物。我们的多学科方法有多个新颖的方面。首先，我们正在使用计算建模和细胞生物学的新组合作为一种有效的方法来预筛选有前途的抗癌药物。其次，在靶向msh2依赖性凋亡通路时，我们靶向的是一个重要的细胞通路，其存在和重要性直到最近才被发现。第三，我们正在针对计算发现的MSH2的特定“死亡”构象，以消除筛选第一步中的大多数化合物并诱导特定的细胞死亡途径。通过这种方法，化合物将被设计为激活自然发生的途径，而不是抑制途径。第四，本项目将化学疗法损伤反应的分子细节计算模型与生物实验紧密结合。公共卫生启示：本研究的最终目标是发现和设计基于msh2依赖性凋亡通路的更安全、更有效的改良化疗药物。

DESCRIPTION (provided by applicant): Computational modeling, cell biological, biophysical, chemical experimentation, and animal models will be combined in a novel approach to prescreening of compounds for drug design, which is rendered to be more efficient and rapid than current approaches. This interdisciplinary study integrates: (i) computational modeling incorporating protein dynamics to screen for compounds that favor a particular protein conformation and with that best induce cell death, followed by refinement to predict more efficient compounds; (ii) chemical synthesis of the most promising compounds; (iii) cell biological experimentation to verify predictions, aid in the refinement of the computational predictions and perform preclinical evaluations; followed by (iv) screening of the most promising compounds in vivo. We are targeting a specific protein, the MMR protein MSH2 (MutS homolog 2), since we have shown that this protein undergoes specific conformational changes in response to DNA damage, specifically due to platinum damage, which ultimately results in the induction of cell death. We are specifically designing compounds that will induce the same conformational changes in MSH2 and ultimately trigger cell-death. Our multi-disciplinary approach has multiple novel aspects. First, we are using a novel combination of computational modeling and cell biology as an efficient way of prescreening promising anticancer drugs. Second, in targeting the MSH2-dependent apoptotic pathway, we are targeting an important cellular pathway whose existence and importance has only recently come to light. Third, we are targeting specific "death" conformations of MSH2, discovered computationally, to eliminate the majority of compounds in the first step of the screen and induce a specific cell death pathway. With this approach, the compounds will be designed to activate a naturally occurring pathway, as opposed to inhibiting a pathway. Fourth, this project closely integrates computational modeling of the molecular details of the response to damage by chemotherapeutics with biological experimentation. PUBLIC HEALTH REVELANCE:The eventual goal of this research is the discovery and design of improved chemotherapeutics, ones that are both safer and more effective, based on a MSH2-dependent apoptotic pathway.