Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches.
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Pearlstein RA, Vaz RJ, Kang J, Chen XL, Preobrazhenskaya M, Shchekotikhin AE, Korolev AM, Lysenkova LN, Miroshnikova OV, Hendrix J, Rampe D
Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches.
Bioorg Med Chem Lett. 2003 May 19;13(10):1829-35.
- PubMed ID
- 12729675 [ View in PubMed]
- Abstract
A data set consisting of twenty-two sertindole analogues and ten structurally diverse inhibitors, spanning a wide range in potency, was analyzed using CoMSiA. A homology model of HERG was constructed from the crystal structure of the open MthK potassium channel. A complementary relationship between our CoMSiA and homology models is apparent when the long inhibitor axis is oriented parallel to the longitudinal axis of the pore, with the tail region pointed toward the selectivity filter. The key elements of the pharmacophore, the CoMSiA and the homology model are: (1) The hydrophobic feature optimally consists of an aromatic group that is capable of engaging in pi-stacking with a Phe656 side chain. Optionally, a second aromatic or hydrophobic group present in some inhibitors may contact an additional Phe656 side chain. (2) The basic nitrogen appears to undergo a pi-cation interaction with Tyr652. (3) The pore diameter (12A+), and depth of the selectivity loop relative to the intracellular opening, act as constraints on the conformation-dependent inhibitor dimensions.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Cisapride Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 45 N/A N/A Details Dofetilide Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 10 N/A N/A Details Pimozide Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 18 N/A N/A Details Sertindole Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 3 N/A N/A Details Terfenadine Potassium voltage-gated channel subfamily H member 2 IC 50 (nM) 56 N/A N/A Details