title: Prospective virtual screening for novel p53-MDM2 inhibitors using ultrafast shape recognition.
abstract: The p53 protein, known as the guardian of genome, is mutated or deleted in approximately 50 % of human tumors. In the rest of the cancers, p53 is expressed in its wild-type form, but its function is inhibited by direct binding with the murine double minute 2 (MDM2) protein. Therefore, inhibition of the p53-MDM2 interaction, leading to the activation of tumor suppressor p53 protein presents a fundamentally novel therapeutic strategy against several types of cancers. The present study utilized ultrafast shape recognition (USR), a virtual screening technique based on ligand-receptor 3D shape complementarity, to screen DrugBank database for novel p53-MDM2 inhibitors. Specifically, using 3D shape of one of the most potent crystal ligands of MDM2, MI-63, as the query molecule, six compounds were identified as potential p53-MDM2 inhibitors. These six USR hits were then subjected to molecular modeling investigations through flexible receptor docking followed by comparative binding energy analysis. These studies suggested a potential role of the USR-selected molecules as p53-MDM2 inhibitors. This was further supported by experimental tests showing that the treatment of human colon tumor cells with the top USR hit, telmisartan, led to a dose-dependent cell growth inhibition in a p53-dependent manner. It is noteworthy that telmisartan has a long history of safe human use as an approved anti-hypertension drug and thus may present an immediate clinical potential as a cancer therapeutic. Furthermore, it could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against variety of cancers. Importantly, the present study demonstrates that the adopted USR-based virtual screening protocol is a useful tool for hit identification in the domain of small molecule p53-MDM2 inhibitors.
authors.affiliation: NanoBio Laboratory, Department of Chemical Engineering, Widener University, Chester, PA, 19013, USA, spatil@widener.edu.
authors.forename: Sachin P
authors.initials: SP
authors.lastname: Patil
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Ballester
authors.forename: Cassidy R
authors.initials: CR
authors.lastname: Kerezsi
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011446:Prospective Studies; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000077333:Telmisartan; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D001562:Benzimidazoles; D001565:Benzoates; D007093:Imidazoles; D008024:Ligands; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2; D000077333:Telmisartan