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

• Published in: Scientific reports 2021-08, Vol.11 (1), p.16580-14, Article 16580
• Main Authors: Aguayo-Ortiz, Rodrigo, Creech, Jeffery, Jiménez-Vázquez, Eric N., Guerrero-Serna, Guadalupe, Wang, Nulang, da Rocha, Andre Monteiro, Herron, Todd J., Espinoza-Fonseca, L. Michel
• Format: Article
• Language: English
• Subjects: 631/154; 631/154/436; 631/154/436/2387; 631/92/314; 631/92/606; Adenosine triphosphatase; Animals; Ca2+-transporting ATPase; Calcium (reticular); Cardiac muscle; Cell activation; Computer applications; Drug delivery; Drug development; Enzyme Activation - drug effects; Giant Cells - enzymology; Heart; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - enzymology; Membrane proteins; Membrane Proteins - drug effects; Membranes; Microsomes - enzymology; Molecular Dynamics Simulation; Molecular Structure; Molecular Targeted Therapy - methods; multidisciplinary; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Phosphatidylcholines; Pluripotency; Protein Domains - drug effects; Proteins; Proteomes; Safety; Sarcoplasmic reticulum; Sarcoplasmic Reticulum - enzymology; Sarcoplasmic Reticulum Calcium-Transporting ATPases - drug effects; Science; Science (multidisciplinary); Small Molecule Libraries - adverse effects; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; Stem cells; Swine; Therapeutic targets; Water
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-96217-7

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 Ca 2+ pump (Sarcoplasmic reticulum Ca 2+ -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.