title: Ensemble-based virtual screening reveals dual-inhibitors for the p53-MDM2/MDMX interactions.
abstract: The p53 protein, a guardian of the genome, is inactivated by mutations or deletions in approximately half of human tumors. While in the rest of human tumors, p53 is expressed in wild-type form, yet it is inhibited by over-expression of its cellular regulators MDM2 and MDMX proteins. Although the p53-binding sites within the MDMX and MDM2 proteins are closely related, known MDM2 small-molecule inhibitors have been shown experimentally not to bind to its homolog, MDMX. As a result, the activity of these inhibitors including Nutlin3 is compromised in tumor cells over-expressing MDMX, preventing these compounds from fully activating the p53 protein. Here, we applied the relaxed complex scheme (RCS) to allow for the full receptor flexibility in screening for dual-inhibitors that can mutually antagonize the two p53-regulator proteins. First, we filtered the NCI diversity set, DrugBank compounds and a derivative library for MDM2-inhibitors against 28 dominant MDM2-conformations. Then, we screened the MDM2 top hits against the binding site of p53 within the MDMX target. Results described herein identify a set of compounds that have been computationally predicted to ultimately activate the p53 pathway in tumor cells retaining the wild-type protein.
authors.affiliation: Department of Physics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Khaled
authors.initials: K
authors.lastname: Barakat
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mane
authors.forename: Douglas
authors.initials: D
authors.lastname: Friesen
authors.forename: Jack
authors.initials: J
authors.lastname: Tuszynski
mesh_terms: D001665:Binding Sites; D018797:Cell Cycle Proteins; D016000:Cluster Analysis; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009687:Nuclear Proteins / Q000378:metabolism*; D025341:Principal Component Analysis; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000032:analysis* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014584:User-Computer Interface
chemical_list: D018797:Cell Cycle Proteins; D008024:Ligands; 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