A novel hypothesis for the binding mode of HERG channel blockers

Biochemical and Biophysical Research Communications
Han ChoeYeon Jin Jang

Abstract

We present a new docking model for HERG channel blockade. Our new model suggests three key interactions such that (1) a protonated nitrogen of the channel blocker forms a hydrogen bond with the carbonyl oxygen of HERG residue T623; (2) an aromatic moiety of the channel blocker makes a pi-pi interaction with the aromatic ring of HERG residue Y652; and (3) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of HERG residue F656. The previous model assumes two interactions such that (1) a protonated nitrogen of the channel blocker forms a cation-pi interaction with the aromatic ring of HERG residue Y652; and (2) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of HERG residue F656. To test these models, we classified 69 known HERG channel blockers into eight binding types based on their plausible binding modes, and further categorized them into two groups based on the number of interactions our model would predict with the HERG channel (two or three). We then compared the pIC(50) value distributions between these two groups. If the old hypothesis is correct, the distributions should not differ between the two groups (i.e., both groups show...Continue Reading

References

Feb 1, 1995·Protein Engineering·A C WallaceJ M Thornton
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Feb 1, 1997·Circulation Research·R S WymoreI S Cohen
Sep 27, 2000·Proceedings of the National Academy of Sciences of the United States of America·J S MitchesonM C Sanguinetti
Nov 8, 2001·European Journal of Pharmacology·K FinlaysonJ S Kelly
Apr 3, 2002·Drug Development and Industrial Pharmacy·Charles S ChengWeifeng Yu
Apr 19, 2002·The Journal of Biological Chemistry·Jose A Sánchez-ChapulaMichael C Sanguinetti
Aug 12, 2003·Proteins·Marcel L VerdonkRichard D Taylor
Dec 31, 2003·The Journal of Biological Chemistry·David FernandezMichael C Sanguinetti
Apr 28, 2004·Cell Calcium·A M Brown
Jul 22, 2004·Molecular Pharmacology·Matthew PerryJohn Mitcheson
Feb 19, 2005·Drug Discovery Today·Alex M Aronov
Mar 8, 2005·Trends in Pharmacological Sciences·Michael C Sanguinetti, John S Mitcheson
Apr 23, 2005·SAR and QSAR in Environmental Research·U Norinder
Jun 21, 2005·Journal of Biomolecular Screening·Arnulf DornChristian Apfel
Jun 28, 2005·Bioorganic & Medicinal Chemistry Letters·Giovanni CianchettaRoy J Vaz

❮ Previous
Next ❯

Citations

Oct 30, 2007·Naunyn-Schmiedeberg's Archives of Pharmacology·Eberhard P ScholzChristoph A Karle
Jun 4, 2013·European Journal of Medicinal Chemistry·Anwar RayanAmiram Goldblum
Sep 2, 2014·Biological & Pharmaceutical Bulletin·Seung Ho LeeBok Hee Choi
Feb 11, 2016·Journal of Computer-aided Molecular Design·Swapnil ChavanIan A Nicholls
Mar 18, 2016·ACS Medicinal Chemistry Letters·Beilei WangLupei Du
Jun 6, 2009·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Su-Hyun JoHan Choe
Feb 20, 2009·European Journal of Pharmacology·Xue Ling ZhaoBao Feng Yang
Oct 12, 2007·Journal of Molecular Graphics & Modelling·Divita GargC Gopi Mohan
Oct 11, 2008·Chemical Biology & Drug Design·Khac-Minh Thai, Gerhard F Ecker
Jun 5, 2016·Cardiac Electrophysiology Clinics·Lasse Skibsbye, Ursula Ravens
Apr 9, 2013·Journal of Enzyme Inhibition and Medicinal Chemistry·N S Hari Narayana MoorthyPedro A Fernandes
Jun 1, 2010·Biochimica Et Biophysica Acta·Etienne ChartrandIsabelle Marcotte
Sep 2, 2016·Journal of Biomolecular Structure & Dynamics·Gülru KayıkSerdar Durdagi
May 4, 2017·Medicinal Research Reviews·Subha Kalyaanamoorthy, Khaled H Barakat
Jun 29, 2007·Bioorganic & Medicinal Chemistry·Stephen R JohnsonPaul Levesque
Oct 11, 2007·Journal of Computational Chemistry·Matteo MasettiMaurizio Recanatini
Jan 2, 2014·Pharmacological Reviews·Gregory SliwoskiEdward W Lowe
Sep 4, 2019·PloS One·Bryan CernudaZafir Buraei
Aug 9, 2011·Journal of Biomolecular Screening·N S Hari Narayana MoorthyPedro A Fernandes
Sep 20, 2012·Physiological Reviews·Jamie I VandenbergAdam P Hill
Apr 14, 2020·European Journal of Medicinal Chemistry·Amanda GarridoChristophe Rochais
Nov 20, 2020·Toxicon : Official Journal of the International Society on Toxinology·Yingyi WangChunhua Yuan

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antipsychotic Drugs

Antipsychotic drugs are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Discover the latest research on antipsychotic drugs here

© 2022 Meta ULC. All rights reserved