Identification of the relationship between the thermodynamic signature of the kinetics of cardiotonic steroids and their cellular effects

• Grant number: 23/09814-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2024
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Cristoforo Scavone
• Grantee: Pedro Azalim Neto
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 21/06009-6 - Neuroplasticity -induced by challenge Na, K-ATPase, Klotho, glutamate, and neuroinflammation signaling cascades to reveal new therapeutic targets for aging and neurodegenerative diseases, AP.TEM

Abstract

In the last 15 years, the rate constant of association and dissociation and, consequently, the residence time of a molecule in its receptor has been addressed as a fundamental description of the in vivo effects of drugs. Furthermore, in some drug-receptor systems, the possibility of relating the intrinsic efficacy of the ligand with its thermodynamic profile was identified, a concept known as thermodynamic discrimination. Both concepts have allowed a deeper characterization of drugs. However, the energy related to the rate constants is given by the difference between and the transition state, without this knowledge the structural and thermodynamic planning of the rate constants is limited. In the interaction between cardiotonic steroids and Na/K-ATPase (NKA), this system has gained prominence in the last decade, due to numerous studies reporting its cytotoxic effects on cancer cells as well as an immunogenic effect, which may involve from the deregulation of cytoplasmic calcium caused by the inhibition of NKA, to an effect due to the activation of the Srckinase signaling pathway, while its proposed anti-inflammatory effects are based on its inhibitory effect on the differentiation of Th0 cells into Th17, as well as the inhibition of the NF-kappaB pathway. In this way, the importance of this work aims to identify whether it is possible that the effects of ECTs are guided, not by their ability to bind to the protein (affinity), but by their kinetics. (AU)