Voltage-gated potassium channel KCNQ2 is responsible for M-currents in neurons and is an important drug target for treating epilepsy and many other diseases and conditions which are characterized by hyper-excitation of neurons, such as pain, Parkinson’s disease, ischemia, hypertension, schizophrenia, and smooth muscle disorders. In animal models, M-current suppression contributes to the development of osteoarthritic pain and neuropathic pain, while KCNQ2 activation relieves neuropathic pain and fibromyalgia. Although several compounds have been developed to directly activate KCNQ2, until recently their activation mechanisms have remained unclear because of the lack of high-resolution structures .
We have designed a new KQCN2 (Kv7.2) Ion Channel Targeted Library of around 4,600 small drug-like molecules that are potential KCNQ2 activity modulators selected with docking-based virtual screening against our proprietary HTS Compound Collection (Fig. 1-2).
The compound selection can be customized based on your requirements, cherry picking is available.
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The in silico screening has been done using recently deposited (cryo-EM) structures of the human KCNQ2 determined in the apo state and in complex with two activators, ztz240 or retigabine, which activate KCNQ2 through different mechanisms. Accordingly, two different binding sites from KCNQ2 complexes PDBID:7CR1 and PDBID:7CR2 have been probed in the virtual screens, resulting in this screening set of potential KCNQ activators selected on the base of top-scored drug-like screening compounds and their intermolecular contacts inside each binding site. PAINS, molecules with bad and toxic groups have been excluded using in-house MedChem filters.
Figure 1. Intermolecular contacts of compound F6497-3483 in the binding site of KQCN2 (PDBID:7CR1)
Figure 2. Intermolecular contacts ofcompound F3411-5347 in the binding site of KQCN2 (PDBID:7CR2)
- Li, X., Zhang, Q., Guo, P. et al. Molecular basis for ligand activation of the human KCNQ2 channel. Cell Res 31, 52–61 (2021)