Molecular Dynamics simulation between human UGT2B10 and putative ligands used in pediatric busulfan-based conditioning regimens prior to hematopoietic stem cell transplantation (HSCT)

- Background Sinusoidal occlusion syndrome (SOS) is a life-threatening complication, arising from the overactivation of hepatic endothelial cells (1-3) after hematopoietic stem cell transplantation (HSCT). A genetic variant situated in the UGT2B10 gene (SNP ID: rs17146905) was associated with the occurrence of SOS (Hazard-ratio=4.7) by our research group (4). UDP-glucuronosyltransferases (UGTs) are crucial in drug metabolism. Prefered substrates of UGT2B10 include tertiary amines: Cotinine, amitriptyline, fluconazole, desloratadine, tamoxifen among other antidepressants, antifungals and chemotherapeutic drugs (6-7). - Hypothesis UGT2B10 may be implicated in the detoxification of hepatoxic molecules present during busulfan-based conditioning regimens prior to HSCT, influencing the level of exposure to potentially liver-threatening compounds - Methods 1. Human UGT2B10 model was obtained with the method of multiple-template homology modeling with MODELLER. 2. Interesting potential UGT2B10 substrates present during busulfan-based conditioning regimens prior to hematopoietic stem cell transplantation (HSCT) were selected based on clinical, chemical and biological criterias. 3. Docking predictions between the putative ligands and UGT2B10 were performed with AutoDock Vina. 4. Positive results, based on the results for the positive control, were selected for further Molecular Dynamics simulations with GROMACS. - Folder Content The folders contains the MD simulations results of 7 complexes, composed of UGT2B10, cofactor UDPGlcA, and putative substrates. A readme file comprising details of the file structure and nomenclature is also included. - References (1) Corbacioglu S. et al. Bone Marrow Transplant. 2018; 53(2):138-145 (2) Bonifazi F. et al. Front Immunol. 2020; 11:489 (3) Dalle et Giralt. Biol Blood Marrow Transplant. 2016; 22(3):400-409 (4) Ansari M. et al. Biol Blood Marrow Transplant. 2020; 26(5): (5) Izukawa et al. Drug Metab Dispos. 2009; 37(8):1759-1768 (6) Kaivosaari et al. Mol Pharmacol. 2007; 72(3):761-768 (7) Kato et al. Drug Metab Dispos. 2013; 41(7):1389-1397

    Organizational unit
    CANSEARCH Research Platform for Pediatric Oncology and Hematology
    Type
    Dataset
    DOI
    10.26037/yareta:o7au7wijvrglnb6nu2k4azkmmy
    License
    Creative Commons Attribution-NonCommercial 4.0 International
    Keywords
    MD, UGT2B10, GROMACS
Publication date13/01/2022
Retention date12/01/2032
accessLevelPublicAccess levelPublic
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duaNoneContract on the use of data
Contributors
  • Uppugunduri Satyanarayana, Chakradhara Rao orcid
  • Robin, Shannon
  • Ben Hassine, Khalil orcid
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