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

SBIR 第一阶段：分子模型作为筛选工具，使用基于多糖的手性固定相分离孤儿药手性化合物的对映体

• 批准号: 1621012
• 负责人: Anil Oroskar
• 金额: $ 22.5万
• 依托单位: Orochem Technologies Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1621012&HistoricalAwards=false
• 关键词: SBIR; Phase; Molecular; Modeling; Screening

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.

这项小型企业创新研究阶段I项目的更广泛的影响/商业潜力是，基于分子建模，用于分离分子相同的分子建模，除了几何差异外，这是纯孤儿药物的开发中。 这些分子彼此之间的分离既重要又具有挑战性，因为一种分子形式可以具有有益的治疗价值，但另一种分子形式充其量可以是良性的，但通常也可能是有毒的。该提议的策略的实施应对新药物的快速开发产生重大影响，尤其是由有限的研发资源制造的药物制造商制定的药物。最终，该项目的成功结果将加速制药公司的药物发现，并允许在市场上提供独特的药物配方，向依靠它们进行治疗并延长其寿命的消费者提供。 I阶段研究项目中的技术目标是开发一个预测分子模型，该模型可以指导在纯化手性分子的试验中，用于制药公司用于药物配方中。在过去的十年中，由于发现某些对映异构体可能通过引起毒性或某些缺陷而对人体产生负面影响，因此药物界的努力已转移到研究纯手性药物而不是外围混合物。由于外星人混合物的有害副作用的可能性，商业重点已转向净化药物以创建对照式手性手性产品。将要构建的建模工具将利用过去几年中开发的重要专有数据Orochem，这是他们开发新的和创新方法的研发活动的一部分，用于分离对映异构体的外星人混合物。初始分子模型将证明手性固定相，流动相和已知由特定系统解决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中对映异构体的构象，因为分子建模输入参数包括有关种族分子中存在的键，角度和二面能量的细节。总体而言，色谱分离的分子模拟将减少通过领导实验研究和制药公司的帮助研究科学家发现这些手性异构体的系统的时间，以鉴定合适的手性固定阶段Apriori。这将减少将新药推向市场的成本和时间。