SBIR Phase I: Molecular Modeling as a Screening Tool to Separate Enantiomers of Chiral Compounds Using Polysaccharide-based Chiral Stationary Phases for Orphan Drugs

这个小企业创新研究I期项目的更广泛的影响/商业潜力是开发一种有效的节省成本的筛选技术，该技术基于分子建模，用于分离纯孤儿药开发中存在的除几何差异外完全相同的分子。 将这些分子彼此分离是重要且具有挑战性的，因为虽然一种分子形式可以具有有益的治疗价值，但另一种分子形式最多可以是良性的，但通常也可以是有毒的。这一拟议战略的实施将对新药的快速开发产生重大影响，特别是那些研发资源有限的制药商正在制定的新药。最终，该项目的成功结果将加速制药公司的药物发现，并允许市场上向依赖它们进行治疗的消费者提供独特的药物配方并延长其寿命。 该第一阶段研究项目的技术目标是开发一种预测性分子模型，该模型可以指导制药公司在药物配方中使用的手性分子纯化实验。在过去的十年中，由于发现某些对映体可能通过引起毒性或某些缺陷对人体产生负面影响，制药界的努力已经转向研究纯手性药物而不是外消旋混合物。由于外消旋混合物可能产生有害的副作用，商业焦点已转向纯化药物以产生对映体纯的手性产物。要建立的建模工具将利用Orochem在过去几年中开发的重要专有数据，作为其研发活动的一部分，用于开发新的和创新的对映体外消旋混合物分离方法。初始分子模型将证明手性固定相、移动的相和已知通过特定系统拆分的对映异构体之间的相互作用。 动态模型将允许以更详细的方式检查手性分离系统内对映异构体的构象，因为分子建模输入参数包括外消旋体分子中存在的键、角和二面角能的细节。总的来说，色谱分离的分子模拟将减少发现用于分离这些手性异构体的系统的时间，通过领导实验研究并帮助制药公司的研究科学家先验地确定合适的手性固定相。这将减少将新药推向市场的成本和时间。

The broader impact/commercial potential of this Small Business Innovation Research Phase I project is to develop an effective cost saving screening technology based on molecular modeling for separating molecules that are identical except for geometric differences, that are present in the development of pure orphan drugs. The separation of these molecules from one another is both important and challenging, since while one molecular form can have beneficial therapeutic value, the other molecular form can at best be benign but often can also be toxic. The implementation of this proposed strategy should have a significant impact on the rapid development of new medicines especially those being formulated by drug manufacturers with limited R&D resources. Ultimately, a successful outcome from this project will accelerate drug discovery in pharmaceutical companies and allow for unique drug formulations to be available in the market to consumers that are relying on them for treatment and to extend their life. The technical objectives in this Phase I research project are to develop a predictive molecular model which can guide experimentation in purifying chiral molecules for pharmaceutical companies to use in drug formulations. Over the past decade, the efforts in the pharmaceutical community have shifted to studying pure chiral drugs rather than racemic mixtures due to the discovery that certain enantiomers may have negative implications on the human body by causing toxicity or certain defects. Owed to the possibility of harmful side effects from racemic mixtures, the commercial focus has turned to purifying pharmaceutical drugs to create an enantio-pure chiral product. The modeling tools to be built will take advantage of significant proprietary data Orochem has developed in the past few years as part of their R&D activities in developing new and innovative methods for the separation of racemic mixtures of enantiomers. The initial molecular model will demonstrate interaction between a Chiral Stationary Phase, mobile phase, and enantiomers known to be resolved by the particular system. The dynamic model will allow examination of conformations of the enantiomer within the chiral separation system in a more detailed fashion since molecular modeling input parameters include detail on the bond, angle, and dihedral energies present in molecules of the racemate. Overall, molecular simulations of chromatographic separations will lessen the time of discovery of systems for separating these chiral isomers by leading experimental investigation and aiding research scientists at pharmaceutical companies to identify suitable chiral stationary phases apriori. This will reduce both the cost and time of bringing new drugs to market.