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Discovery Services

Design and synthesis from hit to clinical candidate

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An experienced interdisciplinary team will work with you on your next clinical candidate.

Drug discovery is an interdisciplinary science where experience is key. Our Medicinal Chemistry team combines over 150 years of relevant experience in the pharma industry. We also partner with leading CROs for specific biological platforms, offering a fully integrated solution to your Discovery needs.

MercachemSyncom delivers high-quality medicinal chemistry services to advance your drug discovery programs: from hit identification to lead optimization and nomination of a clinical candidate. Our team combines an interdisciplinary, highly trained leadership with extensive synthetic resources, such as parallel synthesis and purification, supported by our computational chemistry and in vitro ADME platforms. This combination of expertise allows the rapid multiparameter expansion and optimization of compound series.

For fully integrated drug discovery programs, we have strategic relationships with a network of high-quality partners with expertise in biochemical, cellular and high-content assay development, high throughput screening; structural biology; biophysics and pharmacokinetics. Our network of industrial centers of excellence are accessed under a simple contractual arrangement and with a single project management structure as required by the project.


Hit Generation and Hit-to-Lead Activities

MercachemSyncom has a strong track record in the validation and expansion of hits derived from different screening platforms, including those from high-throughput screens (HTS), fragment screens, DNA-encoded libraries and AI based virtual screens as well as deriving new starting points based on literature and patent  data.

We have ample experience in validating and prioritizing HTS hits, taking into account principles of lead-likeness, synthetic feasibility and intellectual property. Our parallel chemistry and purification platform can play a decisive role in rapid hit expansion, developing both structure-activity and structure-property relationships for hit series. This rapid analog generation allows project teams to make informed decisions on priority and future strategy based on a solid package of data.

In fragment-based drug discovery, chemical starting points are often weak binders, albeit with high ligand-efficient efficiency and structural information. Our medicinal chemistry team includes several fragment-based drug discovery experts, with significant industrial experience of the unique aspects of fragment-based approaches, including the application of biophysical and protein-ligand structural data.


Lead Optimization

Lead optimization requires fine-tuning multiple parameters. MercachemSyncom has an excellent track record of progressing programs through to candidate selection.

Clients also approach us with chemical starting points requiring optimization of a single or multiple parameters, such as solubility, hERG, CYP inhibition etc. Here too, we have been able to efficiently improve the target product profile.

Our in-house SAR database solutions, coupled to DataWarrior and Schrödinger’s LiveDesign interfaces, allow us to effectively mine and analyze project data to efficiently design analogues and progress your lead series toward candidate selection. In many cases we integrate our parallel chemistry and purification infrastructure, generating arrays of analogs to rapidly build structure-activity and structure-property relationships, which we use to design the next generations of ligands.


Computational Chemistry

From bioisosteric replacements to interactive structure and ligand-based drug design, computational chemistry is an integral part of many of our medicinal chemistry projects. Our computational chemists have a solid background in synthetic chemistry and factor synthetic feasibility into their molecular design activities.

At MercachemSyncom, we develop modeling approaches tailored to customer requirements. Our arsenal of molecular modeling software includes Spark, MOE, and Maestro, and we employ state-of-the-art protein-structure visualization software (PyMOL and AxPyMOL) to generate powerful images of your lead molecules bound to the target protein, either from experimental data or from molecular docking.

Our Medicinal Chemistry teams employ advanced data visualization and analysis tools, such as DataWarrior and LiveDesign, which allow for expert property interrogation, trend studies, and R-group analyses. Our workflows allow our chemists to submit design ideas for automatic docking to filter and refine their design hypotheses.

We offer computational chemistry as an integrated component of any medicinal chemistry project and as a stand-alone service.


Library Synthesis

MercachemSyncom has a dedicated team for the design and synthesis of compound arrays, with a focus on novel 3D scaffolds.

High throughput is essential to rapidly explore the chemical space around a hit compound. At MercachemSyncom, we have developed streamlined workflows to optimize our library synthesis. The equipment our chemists use is semiautomated, allowing both a speedy process and room for customization. We have multiple kits available to adapt the setup of the library to your specific needs, whether this is a few compounds or a few hundred.


Integrated Drug Discovery

Through an established centers of excellence network, MercachemSyncom enters into a single contractual agreement with the client that allows access to leading European providers.

MercachemSyncom has a strong European network of centers of excellence to provide integrated drug discovery for our clients. Central to this is a strategic alliance with Axxam [www.axxam.com], based in Milan, Italy, which is a world-class provider of in vitro assay development, screening, and compound profiling services. The combined platforms of MercachemSyncom and Axxam, accessed under a single contractual agreement, provide the core upon which to build gene-to-candidate Discovery programs. Program-specific solutions can also be provided for areas, such as biophysics, pharmacokinetics, pharmacology models, and structural biology.


PROTACs

PROTACs (proteolysis targeting chimeras) are widely regarded as a promising new modality for therapeutic intervention.

PROTAC molecules are typically around 1 kDa in size and often combine two (precursor) molecules with mediocre physicochemical properties (high LogP, low solubility). As a result, the synthesis, analysis, and purification of these compounds can be more challenging than that of traditional small-molecule ligands. Moreover, evidence is emerging that the linker plays the dominant role in PROTAC efficiency & selectivity, and we believe that a parallel approach to producing a large set of linkers will be key to PROTAC’s success.

To address these features, we have developed a modular chemistry toolbox, in which different linking strategies are combined with optimized analytical routines. We have:

  • A selection of E3 ligands (VHL and a series of CRBN analogs);
  • A set of alkyl and PEG linkers with different lengths and composition;
  • Established chemistry to connect these linkers to the E3 ligands, using a variation of couplings;
  • Established chemistry to couple the linkers to the target ligand.

This approach allows for the rapid assembly of a comprehensive set of different PROTAC molecules for any new target.


ADME

We can support your multiparameter medicinal chemistry optimization even further with our in vitro ADME profiling platform.


The following assays are available in house, with further systems either being brought online or sourced via third parties:

Physical/chemical properties:

  • Kinetic solubility (LC-UV)
  • Thermodynamic solubility
  • Lipophilicity (ElogD)
  • Chemical stability

Absorption studies:

  • PAMPA (parallel artificial membrane permeability assay);
  • Caco2-cells, absorption, and/or Pgp inhibition (expected before end of Q3)

Distribution:

  • Plasma protein binding using a rapid equilibrium dialysis (RED) device and plasma from several different species (expected before end of Q3)
  • Plasma stability

Metabolism:

  • Microsomal and hepatocyte stability from different species.
  • Metabolite identification using high-resolution mass spectrometry (Q Exactive Orbitrap, Thermo)

Drug interaction:

  • CYP inhibition screening studies to determine possible drug interactions of compounds (CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4)
  • Time-dependent CYP inhibition studies (Expected before end of Q3)

Our in vitro ADME department also serves as a stand-alone contract research laboratory, where we offer tailor-made assays. In vivo facilities are available as part of our integrated drug discovery services from high-quality third parties under a single contract with us.

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