Abstract
Additional biological protection; blood brain barrier (BBB) to neuronal tissue is essential against invading infections and unwanted chemicals. However, such highly selective transport across the BBB often restricts entry of majority of drug molecules intended for various therapies including thrombotic cerebral ischemia. The inadequate permeation of drugs across BBB and subsequently failure of intended therapies result in finding an effective native transport mechanism. The computational approach in studying protein–protein interactions emerged as one of prospective hope for the identification of proteins (receptors/transporter) towards an effective drug delivery system. Interestingly, low-density lipoprotein receptor proteins-1 (LRP-1) express constitutively in many tissues including BBB plays an important role in the transport of peptides (hormones) believed a candidate transporter for drugs to the neuronal tissue. In this study, earthworm fibrinolytic enzyme (EFE); an effective thrombolyte and its interaction with LRP-1 suggests potential transport mechanism towards entry of drug molecule into neuronal tissue. Fibrinolytic enzyme (PDB Id-1M9U) was docked to LRP1 (PDB Id-1CR8) using Auto Dock tool. Virtual screening following by binding energy calculations suggest a promising interaction of EFE with LRP-1. Further, RMSD and RMSF calculations provide insights and extent of protein-protein interactions (PPIs). Molecular dynamic simulation (MDS) studies were carried out to predict the stability of docked cluster followed by binding mode and surface analysis. Interacting residues in various site/pose were compared with Novel LRP-1 binding peptide 57 and does not show significant similarity. The interacting residues and docking pose in docked cluster suggest LRP-1 a potential transport shuttle for the clot-dissolving drug molecules. We analyzed EFE-LRP-1 interaction and propose LPR-1 mediated endocytosis of EFE across BBB.
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Abbreviations
- AHA:
-
American Heart Association
- RSMD:
-
Root mean square deviation
- RSMF:
-
Root mean square fluctuations
- BBB:
-
Blood–brain barrier
- EFE:
-
Earthworm fibrinolytic enzyme
- MDS:
-
Molecular dynamic simulations
- LPR:
-
Low-density lipoprotein receptor protein
- PPIs:
-
Protein–protein interactions
- GROMACS :
-
Groningen machine for chemical simulations
- PDB:
-
Protein data bank
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The author would like to acknowledge Department of Biotechnology, Acharya Nagarjuna University, Guntur, Andhra Pradesh, India for kind support and providing a facility for proposed study.
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Verma, M.K., Shakya, S. LRP-1 Mediated Endocytosis of EFE Across the Blood–Brain Barrier; Protein–Protein Interaction and Molecular Dynamics Analysis. Int J Pept Res Ther 27, 71–81 (2021). https://doi.org/10.1007/s10989-020-10065-z
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DOI: https://doi.org/10.1007/s10989-020-10065-z