Pharmacophore-based Ion Channel Focused Library

The sequencing of the human genome has identified more than 400 putative ion channels, but only a small fraction of these have been cloned and functionally tested. In recent years, the development of ion channel-targeted drugs has gained great attention due to the widespread tissue distribution of ion channels. In addition, the different physiological consequences of their opening and closing play an important role in almost all physiological activities, such as neural activity, muscle movement, heartbeat, etc.

To overcome this gap, BOC Sciences has designed an original ion channel targeted library of more than 5,500 potential ion channel blockers through a receptor-based approach, with compounds carefully selected from our proprietary HTS compound collection.

Application of Ion Channels

Ion channels have several characteristics that make them particularly suitable for development as drug targets:

• Their opening and closing are directly related to disease
• They can be directly modulated by small molecule compounds
• There is a wide variety of species, and most of which only perform specific functions in specific tissues
• Ion channel drugs are not prone to side effects
• There are clearly observable functional phenomena that can be easily observed: ion flow, which are convenient for high throughput screening of drugs

Figure 1. Models for direct regulation of ion channels by actin. (Shaw, J. E.; Koleske, A. J. 2021)

Pharmacophore-based Ion Channel Focused Library Design

1. To select the best compounds for the library, BOC Sciences uses X-ray data for ten human ion channel targets (in complex with small molecule ion channel modulators) from the available protein databases:
• Glutamate receptor ionotropic, kainate 1 (GRIK1)
• Annexin V
• Potassium channel subfamily K member 10
• Small conductance calcium-activated potassium channel protein 2 (SK2)
• Glycine receptor subunit alpha-3
• Glutamate receptor ionotropic, NMDA 2A (GRIN2A)
• Glutamate receptor 2 (GluR2)
• Ionotropic glutamate receptor GluR5
• Excitatory amino acid transporter 1 (EAAT1)
• Cystic fibrosis transmembrane conductance regulator (CFTR)
2. Firstly, for each of the above complexes, our team has developed an recceptor-based pharmacophore model with various "features" describing the binding mode including H-bond donor, H-bond acceptor, aromatic ring, hydrophobic group, positive or negative charge, where each model contains an "excluded volume". We are able to apply this modeling approach to simulate the atoms of the binding sites around the ligands, thus preventing the compounds from being placed in these spatial sites during the virtual screening
3. Then, we screen the BOC Sciences HTS compound collection against each pharmacophore model with pre-generated compliance, i.e., up to 50 conformations per compound
4. Finally, the resulting potential ion channel modifiers will be carefully filtered through the Rule of Five, PAINS and internal filters to remove molecules with undesired and reactive moieties

Pharmacophore-based Ion Channel Focused Library Characteristics

• We select the drug-like screening compounds targeting ion channels for this screening set, which show the best fit against the corresponding pharmacophore models
• Information on the corresponding target and pharmacophore "fitness" scores is also offered
• Favorable physicochemical parameters and solubility requirements
• No PAINS or toxic substances/unwanted functions: filtered by strict ‘Ro5-like’ physicochemical and most stringent in-house structural filters
• Bioactivity and safety confirmed by preclinical studies and clinical trials
• Structural diversity, medicinal activity, and cellular penetration
• Structural document, IC₅₀, and other chemical and biological data are provided
• All compounds are continually updated
• Compound cherry-picking service is provided

What We Deliver

• Delivered within 2 weeks in any customer-preferred format
• Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
• All compounds have a minimum purity of 90% assessed by ¹H NMR and HPLC
• Analytical data is provided

BOC Sciences provides professional, rapid and high-quality services of Pharmacophore-based Ion Channel Focused Library design at competitive prices for global customers. Personalized and customized services of Pharmacophore-based Ion Channel Focused Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!