Targeting the MSH2-dependent Apoptotic Pathway

描述(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用于药物设计的化合物预筛选的新方法中，该方法比目前的方法更有效和更快。这项跨学科研究包括：(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和最能诱导细胞死亡的化合物，然后进行优化以预测更有效的化合物；(Ii)最有希望的化合物的化学合成；(Iii)细胞生物学实验，以验证预测，帮助完善计算预测并进行临床前评估；(Iv)在体内筛选最有希望的化合物。我们针对的是一种特定的蛋白质，MMR蛋白MSH2(MutS Homolog 2)，因为我们已经证明，这种蛋白质在DNA损伤时经历了特定的构象变化，特别是由于铂损伤，这最终导致细胞死亡。我们正在专门设计一种化合物，这种化合物将在MSH2中诱导相同的构象变化，并最终引发细胞死亡。我们的多学科方法具有多个新颖的方面。首先，我们正在使用计算建模和细胞生物学的新组合作为预先筛选有前景的抗癌药物的有效方法。其次，在针对依赖MSH2的凋亡途径时，我们针对的是一条重要的细胞途径，它的存在和重要性直到最近才被曝光。第三，我们针对通过计算发现的MSH2的特定“死亡”构象，在筛选的第一步消除大多数化合物，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自然发生的途径，而不是抑制途径。第四，该项目将对化疗药物损伤反应的分子细节的计算建模与生物实验紧密结合。公共卫生评论：这项研究的最终目标是发现和设计改进的化疗药物，这种药物基于MSH2依赖的细胞凋亡途径，既安全又有效。

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.