Lead optimization

Once successfully leads, the safe and effective drug candidates will pass lead optimization, is introduced into the preclinical experimental stage.Its related properties usually in multiple DMTA cycle (design - manufacturing - test - analysis) for promotion, such as affinity and selectivity, function mode, which can flourish and ADMET properties.

All lead optimization project of the key lies in the research and development to synthetic compounds and their analogues.New technologies such as microbatch synthesis, not only can take advantage of the combination has been widely used in the field of chemical synthesis, and it also can create, under the condition of low sample weight (a few na l) the demand of rapid analysis of millions of compounds.Brooke's rapifleX MPP can perfectly meet the demand.This instrument can be filtered with the fastest speed, to ensure that the user can control the rapid response and can monitor the whole chemical reaction.By using nuclear magnetic resonance (NMR) and X-ray diffraction (XRD) and MS timsTOF Pro, users can easily under the condition of high sample weight determination of the structure, isomerization and response control, etc. More detailed chemical information.Single crystal X-ray diffraction (XRD) SC can provide three-dimensional connection of the atoms of organic molecules and arrange the details of the pictures.

Lead optimization is crucial to establish a "structure - activity relationship, in order to develop more effective ligand.Such as small Angle X-ray scattering (SAXS) and single crystal X-ray diffraction method of X-ray can provide about the structure of the protein - ligand complexes information, so as to further understand the spatial orientation of ligands.For the reasonable design of selective ligands or effective ligands, is crucial.Nuclear magnetic resonance (NMR) for the smaller proteins, is a kind of perfect complementary technology, it can provide physiological conditions about the combination and the dynamic structure of the information.

Modern lead optimization tend to understand "protein - analyte" as soon as possible the time stability of this kind of complex details.This information can be from the kinetics constants, such as the dissociation constant.Due to the dynamics analysis of the real-time, the tag can be directly observed affinity, IC50, and other features, so the surface plasmon resonance (SPR) technique is very suitable for this stage.In addition, brooke SPR system has a high degree of flexibility, can study at the same time the guide structure and the combination of all kinds of target protein (as many as 31 species), so as to understand its specificity and selectivity.

Not only that, SPR can also provide the enthalpy and entropy of information.The two are the key characteristics in the process of lead optimization.Through the SPR can also be further analysis cofactors and medium conditions, such as pH value of a particular organization on protein - the influence of the interaction between ligands.

Brooke launched a series of mass spectrometry method for the analysis in the process of lead optimization.By using the synchronous accumulation (PASEF) acquisition technology, continuous rupture TimsTOF Pro for in vitro provide highly reliable, sensitive and rapid response research of proteomics.In addition, the plasma spectrum condition, the user can study in orthogonal way "protein - ligand complexes.The method also provides besides, selectivity and affinity binding modes, other information about the chemical metrology.

ADMET properties improvement, will eventually push lead optimization.Brooke SC - XRD, NMR, SPR and MS solution applicable to all kinds of test - completely from the combination of the determination of plasma protein (such as increasing the half-life), analysis of metabolites to distribution and toxicology research.Recently, brooke MALDI imaging toxicological characteristics, on the study of the compounds have been widely recognised as a powerful tool.Brooke magnetic resonance system under the condition of 400 mass-to-charge ratio, MS can reach 290 '000 the quality of the resolution, is the industry leading level.The technology can realize the comprehensive determination of the compound.

In the late stages of lead compounds optimization, the optimized performance of potential lead compounds may be through the use of genetically modified (gm) and disease model for studying the in vivo tests.Under normal circumstances, the experiment should be carried out for small rodents slice research - at some point in the research on animals to remove the tissue.However, brooke preclinical imaging system, such as BioSpec and Skyscan micro - CT, MRI can directly show during the disease, and molecular function related to the specific conditions.Brooke before clinical platform can realize anatomy, function, metabolism and cellular mechanisms of accurate quantitative measurement.Longitudinal experiment not only ensures a high level of data quality, and compared with in vitro tissue section technique, the instant result can affect the optimization decision earlier.In addition, the calibration living creature not only can reduce the use of the number of experimental animals, also can detect living fully functional organ/tissue function mechanism.