The SMD-Relaxed Complex Method for Drug Design

描述（由申请人提供）：大规模活性位点运动的探索及其对配体发现和优化的影响是目前基于结构的药物设计中研究最少的领域之一。所提出的“SMD-松弛复合物”方法解决了以计算有效的方式增加受体构象空间的挑战。操纵分子动力学模拟将被用来从受体的活性位点去除结合的配体，从而加速受体构象空间的采样。对于深埋配体或柔性环的受体，该技术可以增加对大域运动的预测和评估以及活性位点柔性对抑制剂结合的影响的重要见解。所得的受体构象将与QR因子分解算法进行排序，并且非冗余的代表性结构集将用于开发新的药效团模型，并作为宽松的复杂药物设计方案的输入。这种新方法的成功将在锥虫病原体中发现的一种重要RNA编辑酶上得到证明，锥虫病原体是造成几种毁灭性热带疾病的原因。

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.