铅优化

Once leads have been identified successfully, lead optimization starts to bring potent and safe drug candidates into the preclinical phase. Relevant aspects like affinity, selectivity, mode of action, synthesizability and ADMET-properties are typically improved in a multiple design-make-test-analyze (DMTA)-cycles. Bruker’s solutions provide fast, high-quality responses to ensure a high iterative pace in the DMTA-cycles required for the shortest possible time-to-market.

任何铅优化项目的关键要素是易于合成的化合物及其类似物的开发。新型的合成技术（例如Microbatch合成）可以通过组合合成轻松覆盖宽阔的化学空间，但对仅在几种NL的体积上快速分析了快速分析的需求。布鲁克的Rapiflex MPP完美地满足了这一需求，并以最高的速度筛选，以确保对化学反应性景观的快速反应控制和监视。有关结构，异构化和基于较大体积的反应控制的更详细的化学信息可以通过NMR,X-ray diffraction(XRD), and with thetimstof pro ms。Single-crystal X-ray diffraction(SC-XRD) (Link5) delivers a detailed picture of the 3D connectivity and arrangement of the atoms in the organic molecule.

A key element in lead optimization is to establish a structure-activity relationship in order to develop more potent ligands.X射线方法, such as小角度X射线散射（SAXS）和单晶X射线衍射deliver information on the structure of the protein-ligand complex, thus providing insights into spatial orientation of the ligand which is essential to rationally design more selective or potent ligands. Perfectly complementary for smaller proteins,NMRgives structural information about binding and dynamics in physiological conditions.

Modern lead optimization requires details on temporal stability of a protein-analyte complex as early as possible. This information can be derived from the kinetic constants, like dissociation rate constants.Surface Plasmon Resonance(SPR) is highly suited at this stage as the real-time, label-free analysis of the kinetics offers direct insights beyond affinities or IC50. Moreover, the high flexibility of SPR Bruker systems allows to simultaneously investigate the binding of lead structures to up to 31 target proteins offering insights into specificity and selectivity.
此外，SPR允许研究焓和熵的贡献，铅优化过程中的关键特征。可以通过SPR进一步分析辅助因素和媒介条件（例如组织特异性pH）对蛋白质配体相互作用的影响。

布鲁克的mass spectrometry portfolio offers an additional layer of insight relevant during lead optimization. ThetimsTOF Pro利用并行积累的序列碎片（PASEF）采集方法，从而为体外作用模式研究提供了高度可靠，敏感和快速的洞察力。此外，天然MS条件允许以正交方式研究蛋白质配体复合物，此外还提供了有关化学计量的信息，除了亲和力，选择性和结合模式。

Eventually, lead optimization is also driven by improvements ofADMET-properties。Bruker的SC-XRD，NMR，SPR和MS溶液非常适合从与血浆蛋白（例如，增加半寿命）和代谢物分析到分布和毒理学研究的结合评估。最近，我们的马尔代象征has turned out to be especially powerful studying the toxicology profile of compounds. Bruker’s磁共振MS系统deliver a market-leading resolution of > 290’000 mass resolutions at m/z 400, thus enabling a comprehensive mapping of a compound.

有趣的铅化合物优化的公关operties are likely to be tested in in vivo studies using both transgenic and disease models at the later stages of lead optimization. Conventionally, small rodents are used and often require ‘snap shot’ investigations where single time point experiments are carried out on excised tissue. However, Bruker’spreclinical imaging systemssuch as theBioSpec MRI和Skyscan Micro CTcan provide precise events during the disease that may be pertinent to the particular efficacy of the molecule. Bruker’s preclinical platform provides the ability to measure quantitatively and precisely anatomical, functional, metabolic and cellular mechanisms. The high data quality is ensured by longitudinal experiments where live results can influence the decision making much earlier compared to ex vivo tissue assessments. In addition, temporal in vivo biomarkers assessment within animal not only reduces total numbers of animals used but provides information on mechanisms in the intact fully functioning organ/tissue.