title: Discovery of new human epidermal growth factor receptor-2 (HER2) inhibitors for potential use as anticancer agents via ligand-based pharmacophore modeling.
abstract: To discover potential antitumor agents directed toward human epidermal growth factor receptor-2HER2/ErbB2 overexpression in cancer, we have explored the pharmacophoric space of 115 HER2/ErbB2 inhibitors. This identified 240 pharmacophores which were subsequently clustered into 20 groups and cluster centers were used as 3D-pharmacophoric descriptors in QSAR analysis with 2D-physicochemical descriptors to select the optimal combination. We were obliged to use ligand efficiency as the response variable because the logarithmic transformation of bioactivities failed to access self-consistent QSAR models. Two binding pharmacophore models emerged in the optimal QSAR equation, suggesting the existence of distinct binding modes accessible to ligands within the HER2/ErbB2 binding pocket. The QSAR equation and its associated pharmacophore models were employed to screen the National Cancer Institute (NCI) and Drug Bank databases to search for new, promising, and structurally diverse HER2 inhibitory leads. Inhibitory activities were tested against HER2-overexpressing SKOV3 Ovarian cancer cell line and MCF-7 which express low levels of HER2. In silico mining identified 80 inhibitors out of which four HER2 selective compounds inhibited the growth of SKOV3 cells with IC50 values < 5μM and with virtually no effect in MCF-7 cells. These lead compounds are excellent candidates for further optimization.
authors.affiliation: Hamdi Mango Research Center for Scientific Research, The University of Jordan, Amman 11942, Jordan. Electronic address: hibazalloum@gmail.com.
authors.forename: Hiba
authors.initials: H
authors.lastname: Zalloum
authors.affiliation: ACDIMA BioCenter, Amman 11190, Jordan.
authors.forename: Rabab
authors.initials: R
authors.lastname: Tayyem
authors.affiliation: Hamdi Mango Research Center for Scientific Research, The University of Jordan, Amman 11942, Jordan.
authors.forename: Basha'er Abu-
authors.initials: BA
authors.lastname: Irmaileh
authors.affiliation: Department of Biopharmceutics and Clinical Pharmacy, Faculty of Pharmacy, The University of Jordan, Jordan.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Bustanji
authors.affiliation: Department of Pharmacology, Faculty of Medicine, The University of Jordan, Jordan.
authors.forename: Malek
authors.initials: M
authors.lastname: Zihlif
authors.affiliation: ACDIMA BioCenter, Amman 11190, Jordan; Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Jordan.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Mohammad
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Jordan.
authors.forename: Talal Abu
authors.initials: TA
authors.lastname: Rjai
authors.affiliation: Department of Chemistry, Faculty of Science, The University of Jordan, Amman 11942, Jordan Amman 11942, Jordan. Electronic address: mmubarak@ju.edu.ju.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Mubarak
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D012984:Software; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Human epidermal growth factor receptor-2 (HER2); In silico screening; Pharmacophore modeling; Quantitative structure–activity relationship (QSAR)