In order to get a comprehensive view of the properties of the selected hit clusters, singletons, and more advanced derivatives generated during the Hit-2-Lead phase, we profile our compounds using biochemical assays, cellular assays, and biophysical methods to get a reliable overview of the strengths and optimization requirements of the chemical matter. In addition, we analyze the binding mode of selected derivatives by X-ray structure determination to support the optimization process.
With numerous years of experience in Big Pharma drug discovery, NUVISAN’s scientists are able to help you in moving lead generation and optimization campaigns forward by applying target structure-inspired ligand design, typically supported by Xray crystallography, CryoEM and a broad variety of biophysical methods. These structure-elucidating techniques enable us to help you to understand the structure-activity relationships (SAR) from the early stage of a hit-to-lead project until the later stages of the optimization. Such structural evidence helps to understand the complex interplay of polar interactions, hydrophobic properties, dynamic features, displacement, or inclusion of water molecules that drive binding affinity and thereby strongly accelerate cycle times and reduce the number of derivatives to be synthesized to reach the goal.
We have long-standing expertise in the hit-selection process, assessment, modification and rapid generation of a viable lead.
We are drug-hunters, enabling multi-dimensional lead series optimization with short cycle-times in close collaboration with computational compound design.
BEST-IN-CLASS LIFE SCIENCE CHEMISTRY CAPABILITIES
Efficient design and synthesis of high-quality test compounds and chemical probes.
Close interaction with lead discovery in screening hit-list evaluation and long-standing expertise in the Hit-2-Lead process (hit selection, assessment, and modification).
Rapid development of different clusters into viable lead structures to fit your lead structure profile.
Strong drug-hunting attitude within the Lead-2-Candidate process, short cycle-times in multi-dimensional lead optimization programs.
OPTIMIZATION OF MOLECULAR PROPERTIES IS A TEAM EFFORT
Close collaboration with computational compound design, therapeutic research functions (in vitro, ex-vivo, in vivo studies for your target/ indication of interest) and preclinical compound profiling (DMPK property optimization) to identify a preclinical candidate according to an agreed target product profile.
Application of state-of-the-art methodologies (photochemistry, electrochemistry, final stage diversification) to quickly synthesize the target compounds of interest.
First-rate expertise in new modalities (e.g. PROTACs, ADCs) and modalities beyond small molecules (e.g. peptides).
UPSCALING & ROUTE SCOUTING
We synthesize your API or intermediate on large scale (up to 500g).
Route scouting and synthesis route optimization for your API or intermediates.
Special technology capabilities include e.g. high-pressure reactions, photochemistry, hydrogenation, carbonylation, flow chemistry.
In our Separation Technology Laboratories (STL) NUVISAN can perform fast automated as well as customized purification of drug candidates and intermediates, using a variety of different methodologies such as SFC or MS-guided automated preparative HPLC.
Separation of stereoisomers on analytical or preparative scale can also be provided.
We offer the whole range of efficient and flexible small sample single applications and/or batch-wise purifications of test compounds and intermediates.
NUVISAN has access to modern and well-equipped NMR laboratories, where we combine comprehensive structure elucidation expertise with state-of-the-art techniques.
NMR measurements are performed on one of our five Bruker machines, with up to 600 MHz equipped with CryoProbe technology, routinely for the following nuclei: 1H, 13C, 15N, 19F, 31P (other nuclei on request). 2D NMR services are also offered such as COSY, NOESY, TOCSY, ROESY, HSQC and HMBC.
Together with scientists from the Structural Biology group, we routinely study ligand binding to proteins using standard methods such as STD, WaterLOGSY and SOFAST-HSQC. Furthermore, crystal structure determination of small molecules is possible, e.g., to determine the absolute configuration.
Mass Spectrometry and Optical Spectroscopy
In our multifaceted mass spectrometry laboratories, we offer state-of-the-art techniques like ESI, EI, CI, APCI, UPLC/MS, LC/MS and GC/MS.
We perform our measurements on single-quad MS for routine analytics, while for advanced analytical challenges high-resolution TOF and QTOF MS are used.
Our additional high-throughput assays allow a quick measurement for library quality control and the validation of screening hits. Special assays (e.g. for Lipidomics studies) are available on request.
We also offer a wide range of optical methods supporting structure elucidations like FT/IR, IR, optical rotation, ECD and UV/VIS.
For the lead optimization of drug candidates, we measure and interpret a range of physicochemical parameters for target molecules.
Our very efficient high-throughput assays allow a first determination of solubility and lipophilicity for small compound amounts typical of early drug discovery.
We also offer advanced solubility measurements of drugs in single assays with simulated intestinal fluids (FaSSIF, FeSSIF, FaSSGF) and/or formulary solvents (PEG, Tween, HP-β-Cyclodextrine, oil etc.).
Next to that, we provide a broad range of stability assays under different conditions such as hydrolytic, oxidative, or thermal stability, stability against thiols (cysteine, glutathione), stability in simulated gastric fluids and plasma stabilities in human, rat, or mouse.
The photometric determination of acid dissociation constants (pKa) completes our large portfolio of physicochemical determinations for early lead optimization processes.
Early insights into the Mode of Action of the candidate help to de-risk projects by ensuring on-target activity. We identify target engagement / pharmacodynamic biomarkers based on in-depth studies of the target biology using literature searches as as well as bioinformatic analyses.
NUVISAN’s early profiling of in vitro ADME properties of your molecules are the initial steps to characterize lead structures in vitro and identify relevant drug metabolism and pharmacokinetic liabilities. The aim is to identify suitable compounds for in vivo pharmacodynamic and pharmacokinetic studies. For this purpose, we typically use our standard NUVISAN state-of-the-art or customer designed high-throughput assays, designed to evaluate the metabolic stability (liver microsomes and hepatocytes), permeability and efflux (Caco-2 cells) as well as CYP inhibition of major enzyme isoforms (in human liver microsomes).
NUVISAN’s phenotypic small molecule drug screens allow for the unbiased identification of novel targets and drug candidates. A key challenge of phenotypic screens is the subsequent identification of the direct drug target. Recent advances in Proteomics and Functional Genomics have strongly increased the chances of successful target deconvolution.
We have successfully combined CRISPR-based approaches and proteomics (Thermal Proteome Profiling; CETSA-MS) to identify drug targets.
NUVISAN can offer a wide panel of different in vitro as well as in vivo models to understand the biology of your oncology programs and to unravel molecular drivers of efficacy for your molecules.
Through our long-standing experience with different drug targets, we have developed capabilities to design and implement novel mechanistic cellular assays in support of the lead optimization screening tree. With these developments NUVISAN expects to help you to get early insights into the Mode of Action of your molecules and to de-risk your projects by ensuring on-target activity. Together we will identify target engagement / pharmacodynamic biomarkers based on in-depth studies of the target biology using literature searches as well as bioinformatic analyses.