Lead Optimization

一旦成功识别出潜在客户，铅优化就开始将有效和安全的候选药物带入临床前阶段。相关方面诸如亲和力，选择性，作用方式，综合性和助攻性能通常在多个设计策略 - 测试分析（DMTA） - 环节中得到改善。Bruker的解决方案提供了快速，高质量的响应，以确保以最短的上市时间所需的DMTA-Cycles迭代速度。

A crucial element for any lead optimization project is the development of easily synthesizable compounds and analogs thereof. Novel synthetic technologies like microbatch synthesis allow to easily cover a broad chemical space by combinatorial synthesis but create the demand for the fast analysis of millions of compounds at volumes of a few nl only. Bruker’srapifleX MPPperfectly addresses this need and screens at highest pace to ensure rapid reaction control and surveillance of the chemical reactivity landscape. More detailed chemical information regarding structure, isomerization and reaction control based on larger volumes can easily be assessed byNMR，，，，X射线衍射（xrd），然后timsTOF Pro MS。单晶X射线衍射（SC-XRD）（link5）提供了有机分子中原子的3D连通性和排列的详细图片。

铅优化的关键要素是建立结构活性关系，以开发更多有效的配体。X-ray methods， 如small angle X-ray scattering(SAXS) andsingle-crystal X-ray diffractiondeliver 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,NMR提供有关在生理条件下结合和动力学的结构信息。

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.表面等离子体共振（SPR）在此阶段非常适合（SPR），因为对动力学的实时无标签分析提供了超越亲和力或IC50的直接见解。此外，SPR Bruker系统的高灵活性允许同时研究铅结构与多达31个靶蛋白的结合，从而提供了对特异性和选择性的见解。
Additionally, SPR allows to investigate the enthalpic and entropic contribution, key characteristics in lead optimization processes. The influence of co-factors and medium conditions such as tissue-specific pH on a protein-ligand interaction can further be analyzed by SPR.

布鲁克的质谱投资组合在铅优化过程中提供了相关的额外洞察力。这timsTOF Promakes use of the Parallel Accumulation Serial Fragmentation (PASEF) acquisition method, thus offering highly reliable, sensitive and fast insights into proteomics for in vitro mode of action studies. Furthermore, native MS-conditions allow to investigate protein-ligand complexes in orthogonal fashion, additionally providing information on stoichiometry besides affinities, selectivity and binding modes.

最终，铅优化也是由改进的驱动副业。布鲁克的SC-XRD, NMR, SPR and MS solutions are perfectly suited for the investigation all the way from binding assessment with plasma proteins (e.g. for increase of half-life) and metabolite analysis to distribution and toxicology studies. Most recently, ourMALDI-imagining事实证明，研究化合物的毒理学特征特别有力。布鲁克的magnetic resonance MS systemsdeliver a market-leading resolution of > 290’000 mass resolutions at m/z 400, thus enabling a comprehensive mapping of a compound.

具有优化特性的有趣铅化合物可能在铅优化的后期使用转基因和疾病模型在体内研究中进行测试。通常，使用小啮齿动物，通常需要进行“快照射击”调查，在切除组织上进行单个时间点实验。但是，布鲁克的临床前成像系统such as theBiospec MRIandSkyscan micro CT可以在疾病期间提供与分子特定功效有关的精必威官网体育下载确事件。布鲁克的临床前平台提供了定量和精确解剖，功能，代谢和细胞机制的能力。通过纵向实验，与离体组织评估相比，实时结果可以更早地影响决策，从而确保了高数据质量。此外，动物内的体内生物标志物评估不仅减少了所使用的动物总数，而且还提供了完整功能性的器官/组织中机制的信息。