ChameLogK Assay
By integrating lipophilicity (BRlogD) and polarity (Δlog kwIAM) descriptors, ChameLogK provides a comprehensive view of molecular behavior, enabling the design of oral compounds with an optimal balance of solubility and permeability. o2h has developed and validated this protocol, based on peer-reviewed literature, and is the first to offer it as a service.
What is Chameleonicity
Chameleonicity is the ability of molecules to adapt their shape and polarity depending on the environment:
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In aqueous phases → expose polar surfaces
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In lipophilic phases → fold and present hydrophobic features
This adaptive behavior is critical for bRo5 molecules that often struggle with poor permeability and oral delivery. Measuring it early provides insight into:
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BBB penetration potential
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Access to intracellular targets
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Probability of achieving oral bioavailability
Why ChameLogK Assay Matters in Drug Discovery
The ChameLogK assay offers a novel chromatographic descriptor with clear applications in drug discovery, for example:
Membrane Permeability
Built-in membrane permeability properties to fit with target biology; for example crossing the BBB or efficiently accessing intracellular targets.
Molecular Characterisation
Detailed characterisation of molecules to guide design and create a robust pre-clinical data package.
Biophysical & Cellular Insights
Understand the relationship between biophysical and cell-based results.
Use ChameLogK in DMPK & Drug Discovery
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Helps prioritize oral delivery of complex modalities by flagging molecules capable of switching conformations for better permeability. (ScienceDirect Hrčak)
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Streamlines hit-to-lead optimization, especially for flexible, high molecular weight structures.
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Complements ADME profiling by pairing with BRlogD or Δlogk_WIAM for robust physicochemical characterization.
Figure 1. The graph represents molecular weight vs ChamelogK values Validation & Case Studies
Comprehensive Assay Validation:
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Phenol: Despite its rigidity, showed a reproducible profile.
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Macrocycles: Led by Cyclosporin, showed variable behavior.
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Small Molecules: Unexpected aggregation tendencies observed.
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E3 Ligands: Consistent behavior, possibly involving internal folding or interactions.
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Surprising Findings: Molecules like acetone, caffeine, and diazepam defied expectations.
Key Benefits of ChameLogK Assay
Why Choose o2h discovery?
o2h discovery is proud to be the first in the world to offer the ChameLogK assay to our collaborators. With the capability to quickly and cost-effectively measure chameleonicity, this assay marks a significant advancement in evaluating complex molecules such as PROTACs and in optimizing their properties. As pioneers of this approach, o2h has conducted a rigorous validation process that underscores both the reliability of the assay and our commitment to delivering impactful, trustworthy solutions for drug discovery. The assay has been validated with 55 compounds, including macrocycles, non-macrocyclic compounds, and PROTAC molecules, and has demonstrated clear versatility and effectiveness in guiding the design of bioavailable compounds beyond Rule of Five (Ro5) constraints.
To learn more about the ChameLogK assay or discuss how it can support your drug discovery program, contact us at discovery@o2h.com.
Our Support for Your Program Goes Further
PROTAC Toolbox:
Ready-to-use ligands & linkers for degrader design
DMPK Services:
In-vitro ADME and PK studies to complement chameleonicity profiling
Medicinal Chemistry Expertise:
Hit-to-lead and lead optimization programs
FAQs
How is the ChameLogK assay different from traditional permeability assays (e.g., PAMPA, Caco-2)?
Unlike PAMPA or Caco-2, which measure permeability in artificial or cellular systems, ChameLogK quantifies chameleonicity, a compound’s ability to adapt its shape and polarity. This makes it especially useful for complex molecules like PROTACs and macrocycles where traditional assays often fall short.
What types of molecules can be tested?
The assay is designed for Beyond Rule of 5 (bRo5) molecules such as PROTACs, molecular glues, macrocycles, peptides, and other flexible, high-MW compounds.
What makes measuring chameleonicity valuable for bRo5 molecules?
Many bRo5 molecules fail due to poor absorption. Quantifying chameleonicity helps flag promising candidates for oral delivery early in discovery. (APC Journals)
Can ChameLogK be integrated with my existing DMPK and ADME studies?
Yes. It complements in vitro ADME and PK assays by providing additional insight into solubility–permeability balance, helping you build a stronger preclinical data.
Can ChameLogK help predict blood–brain barrier (BBB) penetration?
Yes. Since chameleonicity is linked to a molecule’s ability to shield polarity, ChameLogK provides useful predictive insight into BBB penetration potential.
