Bruker
Produkte & Lösungen
Anwendungen
Service
News & Events
Über uns
Karriere
Drug Discovery

Lead Optimization

Bruker’s product suite delivers high quality, data-rich information to make the rational decisions in an efficient lead optimization process.

Überblick

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.

Picture provided by Maximilian Benz

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’s rapifleX MPP  perfectly 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 by NMR , X-ray diffraction (XRD), and with the timsTOF 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-ray methods, such as small angle X-ray scattering (SAXS) and single-crystal X-ray diffraction  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, NMR gives 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.
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.
 

Bruker’s mass spectrometry portfolio offers an additional layer of insight relevant during lead optimization. The timsTOF Pro makes 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.

Eventually, lead optimization is also driven by improvements of ADMET-properties. Bruker’s 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, our MALDI-imagining has turned out to be especially powerful studying the toxicology profile of compounds. Bruker’s magnetic resonance MS systems deliver a market-leading resolution of > 290’000 mass resolutions at m/z 400, thus enabling a comprehensive mapping of a compound.

Interesting lead compounds with optimized properties 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’s preclinical imaging systems such as the BioSpec MRI and Skyscan micro CT can 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.  

Zugehörige Produkte

Related Products

D8 VENTURE

D8 VENTURE - der Standard für Qualität und Vielseitigkeit in Single Crystal XRD
D8 ENTDECKEN

D8 DISCOVER Familie

Die D8 DISCOVER-Familie ist die ultimative Multi-Purpose-Röntgendiffraktometer-Plattform mit führenden Technologiekomponenten. Es ist für die strukturelle Charakterisierung der gesamten Palette von Materialien von Pulvern, polykristallinen Materialien bis hin zu epitaxialen mehrschichtigen Dünnschichten konzipiert.

NMR Systeme

NMR Systeme ermöglichen informationsreiche, nicht-invasive und quantitative Analysen. Sie liefern detaillierte Informationen über molekulare Struktur, dynamische Prozesse und ermöglichen die direkte Beobachtung chemischer Reaktionen.
rapifleX MALDI PharmaPulse

rapifleX® MALDI PharmaPulse®

The rapifleX® MALDI PharmaPulse® (MPP) enhances label-free HTS combining the unambiguousness of mass spectrometry with the required speed to comb through large compound libraries of millions of substances.
timsTOF Pro

timsTOF Pro

The new standard for 4D-Proteomics™ delivers revolutionary improvements in scan speed, with enhanced specificity and high sensitivity, using TIMS powered by PASEF® technology.
scimaX

scimaX

scimaX is powered by 2xR MRMS technology, bringing the "high hanging fruit" within easy reach.
NANOSTAR

NANOSTAR

Der NANOSTAR ist mit seiner unvergleichlichen Modularität das ideale Werkzeug zur Charakterisierung von Nanostrukturen von 1 nm bis ca. 125 nm und nanostrukturierten Oberflächen durch SAXS, GISAXS und Nanography.
SPR-32 Pro

Sierra SPR-32 Pro

From initial screening to detailed kinetic characterization and thermodynamics measurements, Sierra SPR-32 Pro enables high-throughput SPR analysis of molecular interactions.
Fourier 80

Fourier 80

Aufbauend auf jahrzehntelanger Erfahrung bei der Entwicklung hochwertiger NMR-Instrumente hat Bruker die leistungsstarke NMR-Spektroskopie in kompakter, kosteneffizienter Form neu konzipiert.

BioSpec 3T

Auf einem translationalen Feld von 3 Tesla erweitert der BioSpec 3T das Angebot an Mehrzweck-, präklinischen MRT- und MRS-Systemen in einem kompakten, einfach zu verortenden Standortraum.

SKYSCAN 1272

Hochauflösendes MicroCT an der Bankplatte mit Vibrationsisolierung, CCD-Detektor und Mikropositionierungs-Probenstufe.
Präklinische Mikro-Computertomographie

Präklinische Mikro-Computertomographie

Mikro-Computertomographie ermöglicht Röntgenbildgebung in 3D, Identisch zur Methode, die in Krankenhaus-CT-Scans verwendet wird, aber in kleinem Maßstab mit deutlich erhöhter Auflösung. Es liefert Lösungen für 3D-Mikroskopie, bei der sehr feine interne Strukturen von Objekten nicht-invasiv abgebildet.

Webinare

Support

Labscape

Service & Life Cycle Support for Magnetic Resonance and Preclinical Imaging

Bruker’s commitment to provide customers with unparalleled help throughout the buying cycle, from initial inquiry to evaluation, installation, and the lifetime of the instrument is now characterized by the LabScape service concept.

LabScape Maintenance Agreements, On-Site On-Demand and Enhance Your Lab are designed to offer a new approach to maintenance and service for the modern laboratory