title: Endocrine disruption: In silico perspectives of interactions of di-(2-ethylhexyl)phthalate and its five major metabolites with progesterone receptor.
abstract: Di-(2-ethylhexyl)phthalate (DEHP) is a common endocrine disrupting compound (EDC) present in the environment as a result of industrial activity and leaching from polyvinyl products. DEHP is used as a plasticizer in medical devices and many commercial and household items. Exposure occurs through inhalation, ingestion, and skin contact. DEHP is metabolized to a primary metabolite mono-(2-ethylhexyl)phthalate (MEHP) in the body, which is further metabolized to four major secondary metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5-OH-MEHP), mono(2-ethyl-5-oxyhexyl)phthalate (5-oxo-MEHP), mono(2-ethyl-5-carboxypentyl)phthalate (5-cx-MEPP) and mono[2-(carboxymethyl)hexyl]phthalate (2-cx-MMHP). DEHP and its metabolites are associated with developmental abnormalities and reproductive dysfunction within the human population. Progesterone receptor (PR) signaling is involved in important reproductive functions and is a potential target for endocrine disrupting activities of DEHP and its metabolites. This study used in silico approaches for structural binding analyses of DEHP and its five indicated major metabolites with PR.
  
  
  
  Protein Data bank was searched to retrieve the crystal structure of human PR (Id: 1SQN). PubChem database was used to obtain the structures of DEHP and its five metabolites. Docking was performed using Glide (Schrodinger) Induced Fit Docking module.
  
  
  
  DEHP and its metabolites interacted with 19-25 residues of PR with the majority of the interacting residues overlapping (82-95 % commonality) with the native bound ligand norethindrone (NET). DEHP and each of its five metabolites formed a hydrogen bonding interaction with residue Gln-725 of PR. The binding affinity was highest for NET followed by DEHP, 5-OH-MEHP, 5-oxo-MEHP, MEHP, 5-cx-MEPP, and 2-cx-MMHP.
  
  
  
  The high binding affinity of DEHP and its five major metabolites with PR as well as a high rate of overlap between PR interacting residues among DEHP and its metabolites and the native ligand, NET, suggested their disrupting potential in normal PR signaling, resulting in adverse reproductive effects.
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.
authors.forename: Ishfaq A
authors.initials: IA
authors.lastname: Sheikh
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: KACST Innovation Center in Personalized Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.|Department of Obstetrics and Gynecology, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Rola F
authors.initials: RF
authors.lastname: Turki
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia.
authors.forename: Ghazi A
authors.initials: GA
authors.lastname: Damanhouri
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, PO Box 80216, Jeddah, 21589, Kingdom of Saudi Arabia. mabeg51@gmail.com.
authors.forename: Mohd A
authors.initials: MA
authors.lastname: Beg
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
mesh_terms: D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D052244:Endocrine Disruptors / 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; D011980:Receptors, Progesterone / Q000737:chemistry / Q000378:metabolism*
chemical_list: D052244:Endocrine Disruptors; D010795:Phthalic Acids; D010968:Plasticizers; D011980:Receptors, Progesterone; C479069:mono(2-ethyl-5-hydroxyhexyl) phthalate; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate
keywords: 2-cx-MMHP; 5-OH-MEHP; 5-cx-MEPP; 5-oxo-MEHP; DEHP; Docking; MEHP; Progesterone receptor