A Structural Systems Biology Approach to Drug Discovery

药物发现的结构系统生物学方法

基本信息

批准号：
8798517
负责人：
Rommie E Amaro
金额：
$ 62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2016-10-31
项目状态：
已结题

项目摘要

DESCRIPTION (Provided by the applicant) Abstract: With petascale computing power on the immediate horizon, computational studies have the opportunity to make unprecedented contributions to drug discovery efforts. Although ligand flexibility is routinely accounted for in computer-aided drug design (CADD) methodologies, incorporating receptor flexibility and system complexity remains an important challenge. The next frontier in flexible receptor methodologies is the integration of cutting-edge physics-based computational methods into the CADD techniques, in conjunction with the use of more complex biological systems. The incorporation of powerful new predictive theoretical tools into flexible receptor methodologies for ligand discovery and design will provide an important shift to the CADD field, enabling the discovery of novel ligand-binding modes and expediting the estimation of more accurate ligand free energies of binding. My vision is to drive the computer-aided drug design field towards a systems biology approach, where multiple proteins, and the RNAs they bind, are targeted - thus challenging the "one-target, one- disease, one-drug" paradigm. The new approaches I envision will integrate multiple time and length scales and take explicit advantage of the new structural information yielded by these algorithms. These investigations will push important frontiers in our understanding of biology, ultimately opening new pathways to more effective therapeutics.

描述（申请人提供）摘要：随着佩斯卡尔计算能力的直接地平线，计算研究有机会为药物发现工作做出前所未有的贡献。尽管在计算机辅助药物设计（CADD）方法中，通常会考虑配体柔韧性，但结合受体灵活性和系统复杂性仍然是一个重要的挑战。灵活受体方法论的下一个前沿是将基于尖端物理学的计算方法整合到CADD技术中，并结合使用更复杂的生物系统。将强大的新预测理论工具纳入配体发现和设计的灵活受体方法论将为CADD领域提供重要的转变，从而使发现新型配体结合模式并加快了更准确的结合配体配体能量的估计。我的愿景是将计算机辅助的药物设计领域推向系统生物学方法，其中多种蛋白质和它们绑定的RNA是针对目标的 - 因此挑战了“一目标，一疾病，单药”范式。我设想的新方法将整合多个时间和长度尺度，并明确地利用这些算法产生的新结构信息。这些调查将推动我们对生物学的理解的重要边界，最终为更有效的治疗学开辟了新的途径。