Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediat...Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediate cell transformtion. Yet, there has been very little development of therapies to help tackle Ras-related diseased states. The development of small molecules to target Ras proteins to potentially inhibit abnormal Ras-stimulated cell signaling has been conceptualized and some progress has been made over the last 16 or so years. Here, we briefly review studies characterizing Ras protein-small molecule interactions to show the importance and potential that these small molecules may have for Ras-related drug discovery. We summarize recent results, highlighting small molecules that can be directly targeted to Ras using Structure-Based Drug Design (SBDD) and Fragment-Based Lead Discovery (FBLD) methods. The inactivation of Ras oncogenic signaling in vitro by small molecules is currently an attractive hurdle to try to and leap over in order to attack the oncogenic state. In this regard, important features of previously characterized properties of small molecule Ras targets, as well as a current understanding of conformational and dynamics changes seen for Ras-related mutants, relative to wild type, must be taken into account as newer small molecule design strategies towards Ras are developed.展开更多
基于片段的药物设计(Fragment-Based Drug Design,FBDD)是药物研发的主流方法之一。如何高效从海量药物大数据中筛选出具有相似分子片段的药物小分子成为生物化学研究领域的挑战性问题。针对目前人工筛选耗时长、效率低、药物筛选周期...基于片段的药物设计(Fragment-Based Drug Design,FBDD)是药物研发的主流方法之一。如何高效从海量药物大数据中筛选出具有相似分子片段的药物小分子成为生物化学研究领域的挑战性问题。针对目前人工筛选耗时长、效率低、药物筛选周期长等问题,提出一种基于2D模型的药物小分子筛选方法(SMS-2D)。利用计算机自动化筛选出与目标分子片段具有相似片段的药物小分子。实验结果表明:SMS-2D方法能高效地筛选出包含与分子片段具有相似片段的小分子。展开更多
文摘Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediate cell transformtion. Yet, there has been very little development of therapies to help tackle Ras-related diseased states. The development of small molecules to target Ras proteins to potentially inhibit abnormal Ras-stimulated cell signaling has been conceptualized and some progress has been made over the last 16 or so years. Here, we briefly review studies characterizing Ras protein-small molecule interactions to show the importance and potential that these small molecules may have for Ras-related drug discovery. We summarize recent results, highlighting small molecules that can be directly targeted to Ras using Structure-Based Drug Design (SBDD) and Fragment-Based Lead Discovery (FBLD) methods. The inactivation of Ras oncogenic signaling in vitro by small molecules is currently an attractive hurdle to try to and leap over in order to attack the oncogenic state. In this regard, important features of previously characterized properties of small molecule Ras targets, as well as a current understanding of conformational and dynamics changes seen for Ras-related mutants, relative to wild type, must be taken into account as newer small molecule design strategies towards Ras are developed.
文摘基于片段的药物设计(Fragment-Based Drug Design,FBDD)是药物研发的主流方法之一。如何高效从海量药物大数据中筛选出具有相似分子片段的药物小分子成为生物化学研究领域的挑战性问题。针对目前人工筛选耗时长、效率低、药物筛选周期长等问题,提出一种基于2D模型的药物小分子筛选方法(SMS-2D)。利用计算机自动化筛选出与目标分子片段具有相似片段的药物小分子。实验结果表明:SMS-2D方法能高效地筛选出包含与分子片段具有相似片段的小分子。
