In silico interactions of statins with cell death-inducing DNA fragmentation factor-like effector A (CIDEA)

George E Barreto,Janneth Gonzalez,Željko Reiner,Tannaz Jamialahmadi,Valentina Echeverria,Ghulam Md Ashraf,Amirhossein Sahebkar

doi:10.1016/j.cbi.2021.109528

Abstract

Statins are the low-density lipoproteins (LDL)-cholesterol-lowering drugs of first choice and are used to prevent the increased risk of cardiovascular and cerebrovascular diseases. Although some of their effects are well known, little is known about their ability to regulate other lipid-related proteins which control apoptotic mechanisms. The aim of this study was to explore whether statins can bind to cell death-inducing DNA fragmentation factor-like effector A (CIDEA), which might be a possible pleiotropic mechanism of action of these drugs on the modulation of apoptosis and lipid metabolism. The structures of statins were subjected to molecular docking and dynamics with the human CIDEA protein to investigate the interaction pattern and identify which residues are important. The docking results indicated that atorvastatin and rosuvastatin showed the best interaction energy (−8.51 and −8.04 kcal/mol, respectively) followed by fluvastatin (−7.39), pitavastatin (−6.5), lovastatin (−6.23), pravastatin (−6.04) and simvastatin (−5.29). Atorvastatin and rosuvastatin were further subjected to molecular dynamics at 50 ns with CIDEA and the results suggested that rosuvastatin-CIDEA complex had lower root-mean square deviation and root-mean square fluctuation when compared with atorvastatin-CIDEA. Since two arginine residues -ARG19 and ARG22-were identified to be common for the interaction with CIDEA, a single-point mutation was induced in these residues to determine whether they are important for binding interaction. Mutation of these two residues seemed to affect mostly the interaction of atorvastatin with CIDEA, suggesting that they are important for the binding and therefore indicate another possible metabolic mechanism of the pleiotropic effects of this statin.

Highlights

Cell death-inducing DNA fragmentation factor-like effector A (CIDEA) is a member of CIDE proteins family, which is composed of CIDEA, CIDEB and CIDEC/Fsp27
To locate the binding pocket of CIDEA, we initially used the sitefinder plugin in MOE, which was later confirmed by the CASTp server [24], where it showed that the residues SER15, ASP18, ARG9, SER20, SER21, ARG22, HIS73, SER86, GLY87, SER89, and SER90 are parts of the active protein interaction site
We have found that there is a pattern of interaction of these statins with CIDEA that occurred on NH2 by hydrogen bonds at residues ARG19 and ARG22 and ionic bonds in ARG22

Summary

Introduction

Cell death-inducing DNA fragmentation factor-like effector A (CIDEA) is a member of CIDE proteins family, which is composed of CIDEA, CIDEB and CIDEC/Fsp. Cell death-inducing DNA fragmentation factor-like effector A (CIDEA) is a member of CIDE proteins family, which is composed of CIDEA, CIDEB and CIDEC/Fsp27 They are named so because the overexpression of CIDE proteins in different cell types induces caspaseindependent cell death. CIDEA is expressed in the murine brown adipose tissue and human white adipose tissue [3], and much less in mammary glands [4], sebaceous glands in the skin [5], the meibomian glands [6], and the brain [7]. CIDEA expression highly correlates with lipid storage, lipid secretion and fat metabolism in these tissues

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