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ORIGINAL RESEARCH article

Front. Mol. Biosci.
Sec. Molecular Diagnostics and Therapeutics
Volume 11 - 2024 | doi: 10.3389/fmolb.2024.1414119

Molecular dynamics simulation of the brain-isolated single-domain antibody/nanobody from camels through in vivo phage display screening

Provisionally accepted
Behnam Hasannejad-asl Behnam Hasannejad-asl 1Hassan Hashemzadeh Hassan Hashemzadeh 2Farkhondeh Pooresmaeil Farkhondeh Pooresmaeil 1*Mehran Dabiri Mehran Dabiri 3*Mohammad-Reza Pooresmaeil Mohammad-Reza Pooresmaeil 4*Davoud Ahmadvand Davoud Ahmadvand 5,6*Arshad Hosseini Arshad Hosseini 1*
  • 1 Department of Medical Biotechnology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Alborz, Iran
  • 2 Department of Chemistry, Faculty of Science, University of Birjand, Birjand, Iran
  • 3 Department of Parasitology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Alborz, Iran
  • 4 Medical Education Research Center, Guilan University of Medical Sciences, Rasht, Gilan, Iran
  • 5 Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Alborz, Iran
  • 6 Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran

The final, formatted version of the article will be published soon.

    During the last decade, there has been a significant rise in the use of therapeutic antibodies or passive immunotherapy for treating various conditions like inflammation and cancer. However, these proteins face challenges reaching the brain and often require specialized delivery methods such as single-domain antibodies (sdAbs). Traditional antibodies struggle to efficiently cross the blood-brain barrier (BBB), hindering their effectiveness. Receptor-mediated transcytosis (RMT) offers a promising pathway for transporting large molecules essential for brain function and treatment across the BBB. SdAbs and peptide ligands with an affinity for RMT receptors are commonly employed to enhance the transport of biotherapeutics compounds across the BBB. This research used a sdAbs phage-displayed library from 13 camelus dromedarius samples to identify sdABs that specifically bind to and are internalized by human BBB endothelial cells (ECs) through in vivo panning. One sdAb, defined as FB24, was isolated, sequenced, translated into an open reading frame (ORF), and subjected to three-dimensional (3D) modeling. Molecular docking and molecular dynamics simulations were carried out by the HADDOCK web server and GROMACS, respectively, to evaluate the interaction between FB24 and EC receptors in silico. The docking results revealed that FB24 exhibited binding activity against potential EC receptors with -1.7 to -2.7 ranged z score and maintained a stable structure. The docked complex of FB24-RAGE (receptor for advanced glycation end products, also known as advanced glycation end product receptor [AGER]) showed 18 hydrogen bonds and 213 non-bonded contacts. It was chosen for further analysis by molecular dynamics simulations by GROMACS. This complex showed a stable condition, and its root mean square deviation (RMSD) was 0.218 nm. The results suggest that FB24 could serve as a suitable carrier vector for transporting therapeutic and diagnostic agents across the BBB to the brain through a non-invasive route.

    Keywords: Blood-Brain Barrier, Drug delivery, Camelus Single-domain antibody, phage display library, molecular docking, Molecular Dynamics Simulation

    Received: 11 Apr 2024; Accepted: 05 Aug 2024.

    Copyright: © 2024 Hasannejad-asl, Hashemzadeh, Pooresmaeil, Dabiri, Pooresmaeil, Ahmadvand and Hosseini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Farkhondeh Pooresmaeil, Department of Medical Biotechnology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Alborz, Iran
    Mehran Dabiri, Department of Parasitology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Alborz, Iran
    Mohammad-Reza Pooresmaeil, Medical Education Research Center, Guilan University of Medical Sciences, Rasht, 41625, Gilan, Iran
    Davoud Ahmadvand, Neuroscience Research Center, Iran University of Medical Sciences, Tehran, 1449614535, Alborz, Iran
    Arshad Hosseini, Department of Medical Biotechnology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Alborz, Iran

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.