title: Pharmacophore-based screening targeted at upregulated FN1, MMP-9, APP reveals therapeutic compounds for nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma (NpC) is rare in the west but common in Southeast Asia and only a few other locations. With the limited geographic incidence, it is relatively under-studied. It also has as co-determinant the Epstein-Barr virus (EBV), which may adapt to NpC therapies, so not only must a therapeutic compound be found, the discovery process must be rapid, to cope with the changing basis of the EBV. An R-based computer workbench, Mendel, was developed so biologists could quickly upload genomic data, pre-process them, and identify upregulated and downregulated genes. Mendel was used on 10 control and 31 diseased cell lines to discover 3 differentially expressed genes (DEGs) that meet thresholds on fold-changes, 3-clique membership, pathway constraints, and druggability. From the DEGs, we conducted a pharmacophore-based screening of 22,723,923 compounds using protein-protein interaction anchor-residue clusters as binding sites. Of the 4 hits, 3 passed all the ADME-Tox tests. These 3 hit compounds, 6-(4-iminiocyclohexa-2,5-dien-1-ylidene)-4-(thiazol-2-ylcarbamoyl)-1H-pyrimidine-2-thiolate, 1-[4-[2-[(3R)-3-hydroxy-2-oxo-indolin-3-yl]acetyl]phenyl]-3-phenyl-urea, and (2R)-N4-[4-(1-piperidyl)cyclohexyl]morpholine-2,4-dicarboxamide have predicted pIC50 values superior to the current drugs fluorouracil (5-FU) and taxotere, which have side effects and face EBV drug resistance.
authors.affiliation: Brearley School, 610 East 83rd Street, New York, NY 10028, USA. Electronic address: JessicaLai98@gmail.com.
authors.forename: Catherine Jessica
authors.initials: CJ
authors.lastname: Lai
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, 117545 Singapore.
authors.forename: Boon Hunt
authors.initials: BH
authors.lastname: Tay
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002277:Carcinoma; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D000970:Antineoplastic Agents; C067625:FN1 protein, human; D005353:Fibronectins; D009363:Neoplasm Proteins; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Bioinformatics; Docking; Drug discovery; Nasopharyngeal carcinoma; Pharmacophore; Virtual screening