The SMD-Relaxed Complex Method for Drug Design

描述(申请人提供)：探索大规模的活性部位运动，及其对配体发现和优化的影响，是当前基于结构的药物设计中最未被研究的领域之一。提出的“SMD-松弛复合体”方法解决了以计算高效的方式增加受体构象空间的挑战。引导的分子动力学模拟将被用来从受体的活性部位移除结合的配体，从而加快对受体构象空间的采样。对于具有深埋配体或柔性环的受体，该技术可以为预测和评估大域运动以及活性部位灵活性对抑制剂结合的影响增加重要的洞察力。得到的受体构象将用QR因式分解算法进行排序，非冗余的、具有代表性的结构集将被用于开发新的药效团模型，并作为松弛复杂药物设计方案的输入。这一新方法的成功将在锥虫病原体中发现的一种基本RNA编辑酶上得到证明，锥虫病原体是几种毁灭性热带疾病的罪魁祸首。

DESCRIPTION (provided by applicant): The exploration of large-scale active site motions, and their affect on ligand discovery and optimization, is currently one of the most under-investigated areas in structure-based drug design. The proposed "SMD- relaxed complex" method addresses the challenge of increasing the receptor conformational space in a computationally efficient manner. Steered molecular dynamics simulations will be employed to remove a bound ligand from the receptor's active site, thereby accelerating the sampling of the receptor's conformational space. For receptors with deeply buried ligands or flexible loops, this technique could add significant insight into the prediction and evaluation of large domain motions and the effects of active site flexibility on inhibitor binding. The resulting receptor conformations will be ordered with the QR factorization algorithm, and the non-redundant, representative set of structures will be used to develop novel pharmacophore models and as input to the relaxed complex drug design protocol. The success of this new approach will be demonstrated on an essential RNA editing enzyme found in the trypanosomatid pathogens, which are responsible for several devastating tropical diseases.