Journal
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 40, Issue 8, Pages 3428-3450Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2020.1851299
Keywords
Statin; virtual screening; cardiovascular disease; drug repurposing; umbrella sampling
Categories
Ask authors/readers for more resources
This study examined the interactions of statins, ACE inhibitors, antiarrhythmic drugs, and flavonoids with IRE1, ASK1, and JNK1 on a molecular level, finding that statins had the best affinity with ASK1 and JNK1, while flavonoid norizalpinine and antiarrhythmic drug amiodarone showed strong binding interactions with IRE1. Atorvastatin, pitavastatin, norizalpinine, and amiodarone were identified as potential compounds for preventing cardiac dysfunctions caused by ER stress, suggesting avenues for further research in vitro and in vivo.
One of the important causes of cardiac dysfunction is the triggering of apoptosis through the IRE1-JNK signaling pathway due to excessive ER stress (endoplasmic reticulum stress). Although there are various studies on beneficial or harmful side effects of cardiac drugs, knowledge about the molecular mechanism of their interactions on this pathway is very limited. In this study, we investigated interactions of statins, ace inhibitors, antiarrhythmic drugs and flavonoids in IRE1, ASK1(apoptosis signal-regulating kinase 1) and JNK1 at an atomic level in comparison with their well-known inhibitors. The rank of scores obtained from four different docking algorithms (Autodock 4, Autodock Vina, iGEMDOCK and GOLD) were combined so that they could be compared with each other and evaluated together. According to combined results, the most potent compound for each compound group was selected for molecular dynamics simulations, MM/PBSA (molecular mechanics/Poisson-Boltzmann surface area) and umbrella sampling calculations. We observed that the statin group drugs had the best affinity by interacting with ASK1 and JNK1 by having a similar effect with their inhibitors, and atorvastatin and pitavastatin came to the fore. Norizalpinine from the flavonoid group had a strong binding interaction with IRE1, and amiodarone from the antiarrhythmic drug group had high binding affinities with IRE1, ASK1 and JNK1. Our study has shown that atorvastatin, pitavastatin, norizalpinine and amiodarone may have a role in preventing cardiac dysfunctions caused by ER stress and may shed light on further in vitro and in vivo research. Communicated by Ramaswamy H. Sarma
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available