A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins

Abstract Membrane proteins constitute a substantial fraction of the human proteome, thus representing a vast source of therapeutic drug targets. Indeed, newly devised technologies now allow targeting “undruggable” regions of membrane proteins to modulate protein function in the cell. Despite the adv...

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Autores principales:	Rodrigo Aguayo-Ortiz, Jeffery Creech, Eric N. Jiménez-Vázquez, Guadalupe Guerrero-Serna, Nulang Wang, Andre Monteiro da Rocha, Todd J. Herron, L. Michel Espinoza-Fonseca
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/39ac1d8d1b97427ba94cce0ca3901e15
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spelling	oai:doaj.org-article:39ac1d8d1b97427ba94cce0ca3901e152021-12-02T18:51:52ZA multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins10.1038/s41598-021-96217-72045-2322https://doaj.org/article/39ac1d8d1b97427ba94cce0ca3901e152021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96217-7https://doaj.org/toc/2045-2322Abstract Membrane proteins constitute a substantial fraction of the human proteome, thus representing a vast source of therapeutic drug targets. Indeed, newly devised technologies now allow targeting “undruggable” regions of membrane proteins to modulate protein function in the cell. Despite the advances in technology, the rapid translation of basic science discoveries into potential drug candidates targeting transmembrane protein domains remains challenging. We address this issue by harmonizing single molecule-based and ensemble-based atomistic simulations of ligand–membrane interactions with patient-derived induced pluripotent stem cell (iPSC)-based experiments to gain insights into drug delivery, cellular efficacy, and safety of molecules directed at membrane proteins. In this study, we interrogated the pharmacological activation of the cardiac Ca2+ pump (Sarcoplasmic reticulum Ca2+-ATPase, SERCA2a) in human iPSC-derived cardiac cells as a proof-of-concept model. The combined computational-experimental approach serves as a platform to explain the differences in the cell-based activity of candidates with similar functional profiles, thus streamlining the identification of drug-like candidates that directly target SERCA2a activation in human cardiac cells. Systematic cell-based studies further showed that a direct SERCA2a activator does not induce cardiotoxic pro-arrhythmogenic events in human cardiac cells, demonstrating that pharmacological stimulation of SERCA2a activity is a safe therapeutic approach targeting the heart. Overall, this novel multiscale platform encompasses organ-specific drug potency, efficacy, and safety, and opens new avenues to accelerate the bench-to-patient research aimed at designing effective therapies directed at membrane protein domains.Rodrigo Aguayo-OrtizJeffery CreechEric N. Jiménez-VázquezGuadalupe Guerrero-SernaNulang WangAndre Monteiro da RochaTodd J. HerronL. Michel Espinoza-FonsecaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rodrigo Aguayo-Ortiz Jeffery Creech Eric N. Jiménez-Vázquez Guadalupe Guerrero-Serna Nulang Wang Andre Monteiro da Rocha Todd J. Herron L. Michel Espinoza-Fonseca A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins
description	Abstract Membrane proteins constitute a substantial fraction of the human proteome, thus representing a vast source of therapeutic drug targets. Indeed, newly devised technologies now allow targeting “undruggable” regions of membrane proteins to modulate protein function in the cell. Despite the advances in technology, the rapid translation of basic science discoveries into potential drug candidates targeting transmembrane protein domains remains challenging. We address this issue by harmonizing single molecule-based and ensemble-based atomistic simulations of ligand–membrane interactions with patient-derived induced pluripotent stem cell (iPSC)-based experiments to gain insights into drug delivery, cellular efficacy, and safety of molecules directed at membrane proteins. In this study, we interrogated the pharmacological activation of the cardiac Ca2+ pump (Sarcoplasmic reticulum Ca2+-ATPase, SERCA2a) in human iPSC-derived cardiac cells as a proof-of-concept model. The combined computational-experimental approach serves as a platform to explain the differences in the cell-based activity of candidates with similar functional profiles, thus streamlining the identification of drug-like candidates that directly target SERCA2a activation in human cardiac cells. Systematic cell-based studies further showed that a direct SERCA2a activator does not induce cardiotoxic pro-arrhythmogenic events in human cardiac cells, demonstrating that pharmacological stimulation of SERCA2a activity is a safe therapeutic approach targeting the heart. Overall, this novel multiscale platform encompasses organ-specific drug potency, efficacy, and safety, and opens new avenues to accelerate the bench-to-patient research aimed at designing effective therapies directed at membrane protein domains.
format	article
author	Rodrigo Aguayo-Ortiz Jeffery Creech Eric N. Jiménez-Vázquez Guadalupe Guerrero-Serna Nulang Wang Andre Monteiro da Rocha Todd J. Herron L. Michel Espinoza-Fonseca
author_facet	Rodrigo Aguayo-Ortiz Jeffery Creech Eric N. Jiménez-Vázquez Guadalupe Guerrero-Serna Nulang Wang Andre Monteiro da Rocha Todd J. Herron L. Michel Espinoza-Fonseca
author_sort	Rodrigo Aguayo-Ortiz
title	A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins
title_short	A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins
title_full	A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins
title_fullStr	A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins
title_full_unstemmed	A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins
title_sort	multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/39ac1d8d1b97427ba94cce0ca3901e15
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A multiscale approach for bridging the gap between potency, efficacy, and safety of small molecules directed at membrane proteins

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