RT info:eu-repo/semantics/article
T1 Evaluation of Cx43 gap junction inhibitors using a quantitative structure-activity relationship model
A1 Matusevičiūtė, Ramona
A1 Ignatavičiūtė, Eglė
A1 Mickus, Rokas
A1 Bordel Velasco, Sergio
A1 Skeberdis, Vytenis Arvydas
A1 Raškevičius, Vytautas
K1 Biomedicine, general
K1 Biomedicina
K1 Molecular biology
K1 Cardiology
K1 Cardiac surgery
K1 Corazón - Enfermedades
K1 Gap junctions (Cell biology)
K1 Connexins
K1 Cx43
K1 Conductance
K1 Contundancia
K1 Inhibitors
K1 Inhibidores
K1 Docking
K1 Molecular docking
K1 Acoplamiento molecular
K1 2302.21 Biología Molecular
K1 3205.01 Cardiología
K1 32 Ciencias Médicas
AB Gap junctions (GJs) made of connexin-43 (Cx43) are necessary for the conduction of electrical impulses in the heart. Modulation of Cx43 GJ activity may be beneficial in the treatment of cardiac arrhythmias and other dysfunctions. The search for novel GJ-modulating agents using molecular docking allows for the accurate prediction of binding affinities of ligands, which, unfortunately, often poorly correlate with their potencies. The objective of this study was to demonstrate that a Quantitative Structure-Activity Relationship (QSAR) model could be used for more precise identification of potent Cx43 GJ inhibitors. Using molecular docking, QSAR, and 3D-QSAR, we evaluated 16 known Cx43 GJ inhibitors, suggested the monocyclic monoterpene d-limonene as a putative Cx43 inhibitor, and tested it experimentally in HeLa cells expressing exogenous Cx43. The predicted concentrations required to produce 50% of the maximal effect (IC50) for each of these compounds were compared with those determined experimentally (pIC50 and eIC50, respectively). The pIC50ies of d-limonene and other Cx43 GJ inhibitors examined by our QSAR and 3D-QSAR models showed a good correlation with their eIC50ies (R = 0.88 and 0.90, respectively) in contrast to pIC50ies obtained from molecular docking (R = 0.78). However, molecular docking suggests that inhibitor potency may depend on their docking conformation on Cx43. Searching for new potent, selective, and specific inhibitors of GJ channels, we propose to perform the primary screening of new putative compounds using the QSAR model, followed by the validation of the most suitable candidates by patch-clamp techniques.
PB MDPI
SN 2227-9059
YR 2023
FD 2023
LK https://uvadoc.uva.es/handle/10324/66545
UL https://uvadoc.uva.es/handle/10324/66545
LA eng
NO Biomedicines, 2023, Vol. 11, Nº. 7, 1972
NO Producción Científica
DS UVaDOC
RD 11-jul-2024