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08 14, 2023;63 (15): 4888-4899.

Integrated Approach Including Docking, MD Simulations, and Network Analysis Highlights the Action Mechanism of the Cardiac hERG Activator RPR260243.

Flavio Costa, Riccardo Ocello, Carlo Guardiani, Alberto Giacomello, Matteo Masetti
Author Information
  1. Flavio Costa: Dipartimento di Ingegneria Meccanica e Aerospaziale, Sapienza Università di Roma, via Eudossiana 18, 00184 Rome, Italy. ORCID
  2. Riccardo Ocello: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna, via Belmeloro 6, 40126 Bologna, Italy.
  3. Carlo Guardiani: Dipartimento di Ingegneria Meccanica e Aerospaziale, Sapienza Università di Roma, via Eudossiana 18, 00184 Rome, Italy.
  4. Alberto Giacomello: Dipartimento di Ingegneria Meccanica e Aerospaziale, Sapienza Università di Roma, via Eudossiana 18, 00184 Rome, Italy. ORCID
  5. Matteo Masetti: Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna, via Belmeloro 6, 40126 Bologna, Italy. ORCID
PMID: 37504578 DOI: 10.1021/acs.jcim.3c00596

Abstract

hERG is a voltage-gated potassium channel involved in the heart contraction whose defections are associated with the cardiac arrhythmia Long QT Syndrome type 2. The activator RPR260243 (RPR) represents a possible candidate to pharmacologically treat LQTS2 because it enhances the opening of the channel. However, the molecular detail of its action mechanism remains quite elusive. Here, we address the problem using a combination of docking, molecular dynamics simulations, and network analysis. We show that the drug preferably binds at the interface between the voltage sensor and the pore, enhancing the canonical activation path and determining a whole-structure rearrangement of the channel that slightly impairs inactivation.

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MeSH Term

Humans
Ether-A-Go-Go Potassium Channels
Heart
Piperidines
Arrhythmias, Cardiac
ERG1 Potassium Channel

Chemicals

RPR260243
Ether-A-Go-Go Potassium Channels
Piperidines
ERG1 Potassium Channel
Journal Article Research Support, Non-U.S. Gov't

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