title: Human sex hormone-binding globulin as a potential target of alternate plasticizers: an in silico study.
abstract: Currently, alternate plasticizers are used to replace phthalate plasticizers in children's toys, medical equipments and food packaging, due to the adverse effects of phthalate compounds on human health and laws prohibiting their use. Current information regarding the safety and potential adverse effects of alternate plasticizers is limited and recent studies have found alternate plasticizers to display similar characteristics to those observed in phthalate plasticizers. This study was undertaken to evaluate and predict the potential endocrine disrupting activity of the three most commonly used alternate plasticizers: di(2-ethylhexyl)terephthalate (DEHT), tris(2-ethylhexyl)trimellitate (TOTM), and diisononyl hexahydrophthalate (DINCH) against human sex hormone-binding globulin (SHBG) using in silico approaches.
  
  
  
  The crystal structure of human SHBG (Id: 1D2S) was retrieved from Protein Data Bank. PubChem database was searched for the structures of alternate plasticizers, DEHT, TOTM, and DINCH. Docking was performed using Glide (Schrodinger) Induced Fit Docking module.
  
  
  
  Induced Fit Docking of three alternate plasticizer compounds indicated that each of the three compounds fitted well into the steroid binding pocket of SHBG. Docking displays showed interactions of alternate plasticizers with 25-30 amino-acid residues of SHBG; 18-20 amino residues overlapped between the natural ligand, DHT, and the three compounds (commonality of 82-91 %). The hydrogen-bonding interaction of the amino-acid residue, Asn-82, of SHBG was also present in displays of DHT and all the three alternate phthalates. The binding affinity of all the three alternate phthalates was higher than DHT; maximum in DINCH followed by TOTM and DEHT.
  
  
  
  Our results suggested that the three alternate plasticizers have potential to engage the important interacting residues of SHBG and thus interfere in its steroid homeostatic function.
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, 21589, Jeddah, Kingdom of Saudi Arabia. iasheikh@kau.edu.sa.
authors.forename: Ishfaq A
authors.initials: IA
authors.lastname: Sheikh
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, 21589, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Yasir
authors.affiliation: Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Abu-Elmagd
authors.affiliation: Department of Clinical Biochemistry, University of Kashmir, Srinagar, India.
authors.forename: Tanveer A
authors.initials: TA
authors.lastname: Dar
authors.affiliation: KACST Innovation Center in Personalized Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Adel M
authors.initials: AM
authors.lastname: Abuzenadah
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, 21589, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Ghazi A
authors.initials: GA
authors.lastname: Damanhouri
authors.affiliation: Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Qahtani
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, 21589, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Mohd A
authors.initials: MA
authors.lastname: Beg
mesh_terms: D001565:Benzoates / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D010795:Phthalic Acids / Q000737:chemistry / Q000378:metabolism*; D010968:Plasticizers / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D012738:Sex Hormone-Binding Globulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001565:Benzoates; D010795:Phthalic Acids; D010968:Plasticizers; D012738:Sex Hormone-Binding Globulin; C036101:tri-(2-ethylhexyl)trimellitate; C012125:diisononyl phthalate; C053316:di-(2-ethylhexyl) terephthalate
keywords: DEHT; DINCH; Docking; Endocrine disruption; Sex hormone-binding globulin; TOTM