An Effective Virtual Screening Protocol To Identify Promising p53-MDM2 Inhibitors.
The p53-MDM2 interaction is a well-known protein-protein contact, and its disruption is a key event for p53 activation and induction of its oncosuppressor response. The design of small molecules that can block the p53-MDM2 interaction and reactivate the p53 function is a promising strategy for cancer therapy. To date, several compounds have been identified as p53-MDM2 inhibitors, and X-ray structures of MDM2 complexed with several ligands are available in the Brookhaven Protein Data Bank. These data have been exploited to compile a hierarchical virtual screening protocol. The first steps were aimed at selecting a focused library, which was submitted in parallel to docking and pharmacophore model alignment. Selected compounds were subjected to inhibition assays of both cellular vitality (MTT) and p53-MDM2 interaction (ELISA and co-immunoprecipitation), disclosing four nanomolar inhibitors.
Dipartimento di Farmacia-Scienze del Farmaco, Università "A. Moro" Bari , Via Orabona 4, 70125 Bari, Italy.
Paolo
P
Tortorella
Dipartimento di Farmacia-Scienze del Farmaco, Università "A. Moro" Bari , Via Orabona 4, 70125 Bari, Italy.
Antonio
A
Laghezza
Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti , Via dei Vestini 31, 66100 Chieti, Italy.
Milena
M
Durante
Dipartimento di Farmacia, Università "Federico II" Napoli , Via D. Montesano 49, 80131 Napoli, Italy.
Isabel
I
Gomez-Monterrey
Dipartimento di Farmacia, Università di Salerno , Via G. Paolo II 132, 84084 Fisciano, Italy.
Alessia
A
Bertamino
Dipartimento di Farmacia, Università di Salerno , Via G. Paolo II 132, 84084 Fisciano, Italy.
Pietro
P
Campiglia
Dipartimento di Farmacia-Scienze del Farmaco, Università "A. Moro" Bari , Via Orabona 4, 70125 Bari, Italy.
Fulvio
F
Loiodice
Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56100 Pisa, Italy.
Simona
S
Daniele
Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56100 Pisa, Italy.
Claudia
C
Martini
Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti , Via dei Vestini 31, 66100 Chieti, Italy.
Mariangela
M
Agamennone
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding / Q000187:drug effects; D000072756:Protein Conformation, alpha-Helical; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*; D014584:User-Computer Interface
D000970:Antineoplastic Agents; D008024:Ligands; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2