Assessing hERG1 Blockade from Bayesian Machine-Learning-Optimized Site Identification by Ligand Competitive Saturation Simulations.

Journal of Chemical Information and Modeling
Mahdi MousaeiSergei Yu Noskov

Abstract

Drug-induced cardiotoxicity is a potentially lethal and yet one of the most common side effects with the drugs in clinical use. Most of the drug-induced cardiotoxicity is associated with an off-target pharmacological blockade of K+ currents carried out by the cardiac Human-Ether-a-go-go-Related (hERG1) potassium channel. There is a compulsory preclinical stage safety assessment for the hERG1 blockade for all classes of drugs, which adds substantially to the cost of drug development. The availability of a high-resolution cryogenic electron microscopy (cryo-EM) structure for the channel in its open/depolarized state solved in 2017 enabled the application of molecular modeling for rapid assessment of drug blockade by molecular docking and simulation techniques. More importantly, if successful, in silico methods may allow a path to lead-compound salvaging by mapping out key block determinants. Here, we report the blind application of the site identification by the ligand competitive saturation (SILCS) protocol to map out druggable/regulatory hotspots in the hERG1 channel available for blockers and activators. The SILCS simulations use small solutes representative of common functional groups to sample the chemical space for the enti...Continue Reading

References

Jul 1, 1992·European Heart Journal·M ZimmermannA Bloch
Oct 1, 1995·Circulation Research·H J DuffR S Sheldon
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Feb 1, 1997·Circulation Research·R S WymoreI S Cohen
Apr 26, 2002·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·R LeursM Taglialatela
Sep 5, 2002·Proceedings of the National Academy of Sciences of the United States of America·Jun ChenMichael C Sanguinetti
Nov 15, 2002·American Journal of Physiology. Gastrointestinal and Liver Physiology·Edward ParrGary M Mawe
May 9, 2003·American Journal of Physiology. Gastrointestinal and Liver Physiology·A M FarrellyK D Keef
Jul 22, 2004·Molecular Pharmacology·Matthew PerryJohn Mitcheson
Mar 24, 2006·Nature·Michael C Sanguinetti, Martin Tristani-Firouzi
Apr 18, 2006·Biochemical and Biophysical Research Communications·Han ChoeYeon Jin Jang
Aug 19, 2007·Proceedings of the National Academy of Sciences of the United States of America·Matthew PerryMichael C Sanguinetti
Jul 12, 2008·Pharmacology & Therapeutics·Jules C HancoxYi Hong Zhang
Nov 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Matthew PerryMichael C Sanguinetti
Jan 28, 2010·ChemMedChem·Anna StaryBert L de Groot
Aug 27, 2010·Current Medicinal Chemistry·S DurdagiS Y Noskov
Apr 5, 2011·Journal of Chemical Information and Modeling·E Prabhu RamanAlexander D Mackerell
May 17, 2012·Journal of Chemical Information and Modeling·John J IrwinRyan G Coleman
May 30, 2012·Journal of Computational Chemistry·Theresa J FosterOlgun Guvench
Sep 20, 2012·Physiological Reviews·Jamie I VandenbergAdam P Hill
Sep 20, 2012·Journal of Chemical Information and Modeling·Serdar DurdagiSergei Y Noskov
Oct 30, 2012·American Journal of Physiology. Heart and Circulatory Physiology·Giovanni Y Di VeroliMark R Boyett
Nov 14, 2012·Journal of Chemical Information and Modeling·K VanommeslaegheA D MacKerell
Apr 13, 2013·Journal of Computer-aided Molecular Design·G Madhavi SastryWoody Sherman
Jul 3, 2013·Scientific Reports·James KramerArthur M Brown
Nov 20, 2013·Journal of Chemical Information and Modeling·E Prabhu RamanAlexander D MacKerell
Jan 30, 2014·Journal of Medicinal Chemistry·Richard D TaylorAlastair D G Lawson
Feb 19, 2015·Journal of Chemical Information and Modeling·Sirish Kaushik LakkarajuAlexander D MacKerell
Feb 25, 2015·Methods in Molecular Biology·Christina E FallerOlgun Guvench
Mar 1, 2008·Journal of Chemical Theory and Computation·Berk HessErik Lindahl
Mar 18, 2016·European Journal of Medicinal Chemistry·Maryanna E LanningSteven Fletcher
Apr 14, 2016·Scientific Reports·P SaxenaA Stary-Weinzinger
Jun 30, 2016·Journal of Medicinal Chemistry·Geoffrey A HeinzlFengtian Xue
Nov 8, 2016·Nature Methods·Jing HuangAlexander D MacKerell

❮ Previous
Next ❯

Citations

Aug 24, 2021·Journal of Chemical Information and Modeling·Kuo Hao LeeLei Shi
Sep 30, 2021·Nature Communications·Weiguang WangIra Kurtz

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cardiotoxicity

Cardiotoxicity refers to the muscle damage or dysfunction of heart electrophysiology caused by drug intake or due to disease complications. It is a well-known side effect of several cytotoxic drugs, especially of the anthracyclines and can lead to long term morbidity. Here is the latest research.