title: Discovery of novel dual inhibitors against Mdm2 and Mdmx proteins by in silico approaches and binding assay.
abstract: OBJECTIVE
  The p53 protein, also called guardian of the genome, has a key role in cell cycle regulation. It is activated under stressful circumstances, such as DNA damage which results in permanent arrest or cell death. The protein is disabled in several types of human cancer due to over-expression of the two regulators, Mdm2 and Mdmx. As a result, inhibiting Mdm subtypes could reactivate p53 and bring about a promising therapeutic strategy in cancers.
  
  
  METHODS
  Here a structure-based pharmacophore search and docking simulation are presented in order to filter our in-house library which contains 1035 compounds to find novel scaffolds that inhibit Mdm2 and Mdmx concomitantly. Afterwards, fluorescence polarization binding assay was used to obtain inhibition constant of final compounds.
  
  
  RESULTS
  Thirty two ligands were introduced to bioassay as a result of in-silico methods. Twelve of them inhibit both proteins with almost balanced Ki value ranging from 18 to 162μM for Mdm2 and 18 to 233μM for Mdmx. It was observed that all compounds fill Phe19 and Trp23 pockets of Mdm2/x binding sites and form a hydrogen bond with Trp23 pocket's neighbor amino acids in a manner similar to p53 protein. Additionally, it was concluded that Trp23 pocket of Mdmx has a bigger hydrophobic volume comparing with the one of Mdm2.
  
  
  CONCLUSIONS
  Three structure-activity relationship patterns are supposed which one of them presents usefulness features and can be used in future studies. This study presents first qualitative SAR for dual inhibitors against Mdm2/x.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran.
authors.forename: Sahand
authors.initials: S
authors.lastname: Golestanian
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran.
authors.forename: Amirhossein
authors.initials: A
authors.lastname: Sharifi
authors.affiliation: Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Grzegorz M
authors.initials: GM
authors.lastname: Popowicz
authors.affiliation: Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.
authors.forename: Homa
authors.initials: H
authors.lastname: Azizian
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Foroumadi
authors.affiliation: Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Szwagierczak
authors.affiliation: Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. Electronic address: holak@biochem.mpg.de.
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran. Electronic address: amanlou@tums.ac.ir.
authors.forename: Massoud
authors.initials: M
authors.lastname: Amanlou
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Drug design; Dual inhibitors; In silico process; Mdm2 & Mdmx; Qualitative SAR; p53