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的预筛选，该方法比现有方法更有效和快速。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，并最好地诱导细胞死亡，然后进行改进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;随后是（iv）在体内筛选最有希望的化合物。我们正在靶向一种特定的蛋白质，MMR蛋白MSH 2（MutS同源物2），因为我们已经表明，这种蛋白质在响应DNA损伤时会发生特定的构象变化，特别是由于铂损伤，最终导致诱导细胞死亡。我们正在专门设计能够诱导MSH 2发生相同构象变化并最终引发细胞死亡的化合物。我们的多学科方法具有多个新颖的方面。首先，我们正在使用一种新的计算建模和细胞生物学的组合，作为一种有效的方式来预筛选有前途的抗癌药物。第二，在靶向MSH 2依赖性凋亡途径中，我们靶向了一个重要的细胞途径，其存在和重要性最近才被发现。第三，我们正在靶向计算发现的MSH 2的特定“死亡”构象，以在筛选的第一步中消除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天然存在的途径，而不是抑制途径。第四，该项目将化学治疗对损伤反应的分子细节的计算建模与生物实验紧密结合。公共卫生宣传：这项研究的最终目标是发现和设计改进的化疗药物，这些药物基于MSH 2依赖性凋亡途径，更安全，更有效。

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.