Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of a disruptor of the MDM2-p53 protein-protein interaction facilitated by high-throughput in silico docking.

ABSTRACT: NSC 333003 has been identified from the NCI Diversity Set as an inhibitor of the MDM2-p53 protein-protein interaction by in silico docking (virtual screening). Its potency and chemical characteristics render it well suited for lead optimization studies that can result in more potent analogs with improved drug-like properties. Its synthesis was achieved using an acid catalyzed condensation reaction from commercially available benzothiazole hydrazine and pyridyl phenyl ketone in refluxing methanol. Stereochemical implications for this compound are described.

SUBMITTER: Lawrence HR

PROVIDER: S-EPMC2754843 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Identification of a disruptor of the MDM2-p53 protein-protein interaction facilitated by high-throughput in silico docking.

Lawrence Harshani R HR Li Zhenyu Z Yip M L Richard ML Sung Shen-Shu SS Lawrence Nicholas J NJ McLaughlin Mark L ML McManus Gregory J GJ Zaworotko Michael J MJ Sebti Saïd M SM Chen Jiandong J Guida Wayne C WC

Bioorganic & medicinal chemistry letters 20090503 14

NSC 333003 has been identified from the NCI Diversity Set as an inhibitor of the MDM2-p53 protein-protein interaction by in silico docking (virtual screening). Its potency and chemical characteristics render it well suited for lead optimization studies that can result in more potent analogs with improved drug-like properties. Its synthesis was achieved using an acid catalyzed condensation reaction from commercially available benzothiazole hydrazine and pyridyl phenyl ketone in refluxing methanol ...[more]

PMID: 19457663

Similar Datasets

Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction.

Project description:Protein-peptide interactions are often associated with large-scale conformational changes that are difficult to study either by classical molecular modeling or by experiment. Recently, we have developed the CABS-dock method for flexible protein-peptide docking that enables large-scale rearrangements of the protein chain. In this study, we use CABS-dock to investigate the binding of the p53-MDM2 complex, an element of the cell cycle regulation system crucial for anti-cancer drug design. Experimental data suggest that p53-MDM2 binding is affected by significant rearrangements of a lid region - the N-terminal highly flexible MDM2 fragment; however, the details are not clear. The large size of the highly flexible MDM2 fragments makes p53-MDM2 intractable for exhaustive binding dynamics studies using atomistic models. We performed extensive dynamics simulations using the CABS-dock method, including large-scale structural rearrangements of MDM2 flexible regions. Without a priori knowledge of the p53 peptide structure or its binding site, we obtained near-native models of the p53-MDM2 complex. The simulation results match well the experimental data and provide new insights into the possible role of the lid fragment in p53 binding. The presented case study demonstrates that CABS-dock methodology opens up new opportunities for protein-peptide docking with large-scale changes of the protein receptor structure.

| S-EPMC5131342 | biostudies-literature

In silico study of fragile histidine triad interaction domains with MDM2 and p53.

Project description:BACKGROUND:Fragile histidine triad (FHIT) is considered as a member of the histidine triad (HIT) nucleotide-binding protein superfamily regarded as a putative tumor suppressor executing crucial role in inhibiting p53 degradation by MDM2. Accumulating evidences indicate FHIT interaction with p53 or MDM2; however, there is no certain study deciphering functional domains of FHIT involving in the interaction with MDM2 and/or p53. In this regard, such evident interaction can spring in mind determining important domains of FHIT binding to MDM2 with regard to p53. MATERIALS AND METHODS:Since there were not any previous studies appraising complete three-dimensional structures of target molecules, molecular modeling was carried out to construct three-dimensional models of full FHIT, MDM2, P53 and also FHIT segments. Truncated structures of FHIT were created to reveal critical regions engaging in FHIT interaction. RESULTS:Given the shape and shape/electrostatic total energy, FHIT structures (?1-5), (?3-7, ?1), and (?5-7, ?1) appeared to be better candidates than other structures in interaction with full MDM2. Furthermore, FHIT structures (?6-7), (?6-7, ?1), (?4-7, ?1) were considered to be better than other structures in interaction with p53. FHIT truncates that interact with MDM2 presented lower energy levels than FHIT truncates interacting with p53. CONCLUSION:These findings are beneficial to understand the mechanism of the FHIT-MDM2-p53 complex activation for designing inhibitory compounds.

| S-EPMC4162077 | biostudies-literature

Recent Small-Molecule Inhibitors of the p53-MDM2 Protein-Protein Interaction.

Project description:This review presents the last decade of studies on the synthesis of various types of small-molecule inhibitors of the p53- Mouse double minute 2 homolog (MDM2) protein-protein interaction. The main focus is placed on synthetic approaches to such molecules, their cytotoxicity, and MDM2 binding characteristics.

| S-EPMC7179467 | biostudies-literature

Environment-sensitive turn-on fluorescent probes for p53-MDM2 protein-protein interaction.

Project description:A series of probes with a turn-on switch for the p53-MDM2 protein-protein interaction were developed. After careful evaluation, these small molecule fluorescent probes exhibited high practical activity and selectivity in vitro and in cellulo. In particular probe 10, which had a Ki value of 0.03 ?M, displayed much better binding affinity compared to the positive control Nutlin-3, which had a Ki value of 0.23 ?M. These no-wash environment-sensitive turn-on fluorescent probes have been successfully applied to imaging p53-MDM2 interaction in the human lung cancer cell line A549 (wild-type p53) at the micromolar level. Therefore, these fluorescent probes are expected to be used in drug screening and cell staining in p53-MDM2 fields, as well as in pathological and physiological studies of the p53-MDM2 interaction.

| S-EPMC6072338 | biostudies-literature

Competitive binding between dynamic p53 transactivation subdomains to human MDM2 protein: implications for regulating the p53·MDM2/MDMX interaction.

Project description:The interaction between the transactivation domain of p53 (p53TAD) and the N-terminal domain of MDM2 and MDMX plays an essential role for cell function. Mutations in these proteins have been implicated in many forms of cancer. The intrinsically disordered p53TAD contains two subdomains, TAD1 and TAD2. Using NMR spectroscopy, site-directed mutagenesis, and molecular dynamics simulations, we demonstrate that TAD2 directly interacts with MDM2, adopting transient structures that bind to the same hydrophobic pocket of MDM2 as TAD1. Our data show that binding of TAD1 and TAD2 to MDM2 is competitive, which is further supported by the observation that the interaction of TAD2 with MDM2 can be blocked by the small molecule inhibitor nutlin-3. Our data further indicate that TAD2 interacts with MDMX in a fashion very similar to MDM2. Because TAD2 is known to have transcriptional activity, the interaction of TAD2 with MDM2/MDMX may play a direct role in the inhibition of p53 transactivation.

| S-EPMC3436289 | biostudies-literature

Transient protein states in designing inhibitors of the MDM2-p53 interaction.

Project description:Reactivation of p53 by release of the functional protein from its inhibition by MDM2 provides an efficient, nongenotoxic approach to a wide variety of cancers. We present the cocrystal structures of two complexes of MDM2 with inhibitors based on 6-chloroindole scaffolds. Both molecules bound to a distinct conformational state of MDM2 with nM-?M affinities. In contrast to other structurally characterized antagonists, which mimic three amino acids of p53 (Phe19, Trp23, and Leu26), the compounds induced an additional hydrophobic pocket on the MDM2 surface and unveiled a four-point binding mode. The enlarged interaction interface of the inhibitors resulted in extension of small molecules binding toward the "lid" segment of MDM2 (residues 19-23)--a nascent element that interferes with p53 binding. As supported by protein engineering and molecular dynamics studies, employing these unstable elements of MDM2 provides an efficient and yet unexplored alternative in development of MDM2-p53 association inhibitors.

| S-EPMC4104591 | biostudies-literature

Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment.

Project description:Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2-p53 protein-protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase clinical trials for the treatment of human cancers. Here, we review the design, synthesis, properties, preclinical, and clinical studies of these clinical-stage MDM2 inhibitors.

| S-EPMC4329994 | biostudies-literature

An Application of Fit Quality to Screen MDM2/p53 Protein-Protein Interaction Inhibitors.

Project description:: The judicious application of ligand or binding efficiency (LE) metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Here we report for the first time the use of LE based metric, fit quality (FQ), in virtual screening (VS) of MDM2/p53 protein-protein interaction inhibitors (PPIIs). Firstly, a Receptor-Ligand pharmacophore model was constructed on multiple MDM2/ligand complex structures to screen the library. The enrichment factor (EF) for screening was calculated based on a decoy set to define the screening threshold. Finally, 1% of the library, 335 compounds, were screened and re-filtered with the FQ metric. According to the statistical results of FQ vs activity of 156 MDM2/p53 PPIIs extracted from literatures, the cut-off was defined as FQ = 0.8. After the second round of VS, six compounds with the FQ > 0.8 were picked out for assessing their antitumor activity. At the cellular level, the six hits exhibited a good selectivity (larger than 3) against HepG2 (wt-p53) vs Hep3B (p53 null) cell lines. On the further study, the six hits exhibited an acceptable affinity (range of Ki from 10² to 10³ nM) to MDM2 when comparing to Nutlin-3a. Based on our work, FQ based VS strategy could be applied to discover other PPIIs.

| S-EPMC6321222 | biostudies-literature

Energetic Landscape of MDM2-p53 Interactions by Computational Mutagenesis of the MDM2-p53 Interaction.

Project description:The ubiquitin ligase MDM2, a principle regulator of the tumor suppressor p53, plays an integral role in regulating cellular levels of p53 and thus a prominent role in current cancer research. Computational analysis used MUMBO to rotamerize the MDM2-p53 crystal structure 1YCR to obtain an exhaustive search of point mutations, resulting in the calculation of the ??G comprehensive energy landscape for the p53-bound regulator. The results herein have revealed a set of residues R65-E69 on MDM2 proximal to the p53 hydrophobic binding pocket that exhibited an energetic profile deviating significantly from similar residues elsewhere in the protein. In light of the continued search for novel competitive inhibitors for MDM2, we discuss possible implications of our findings on the drug discovery field.

| S-EPMC4798270 | biostudies-literature

Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapy: Progress and Challenges.

Project description:MDM2 is a primary cellular inhibitor of p53. It inhibits p53 function by multiple mechanisms, each of which, however, is mediated by their direct interaction. It has been proposed that small-molecule inhibitors designed to block the MDM2-p53 interaction may be effective in the treatment of human cancer retaining wild-type p53 by reactivating the p53 tumor suppressor function. Through nearly two decades of intense efforts, a number of structurally distinct, highly potent, nonpeptide, small-molecule inhibitors of the MDM2-p53 interaction (MDM2 inhibitors) have been successfully designed and developed, and at least seven such compounds have now been advanced into human clinical trials as new anticancer drugs. This review offers a perspective on the design and development of MDM2 small-molecule inhibitors and discusses early clinical data for some of the MDM2 small-molecule inhibitors and future challenges for the successful clinical development of MDM2 inhibitors for cancer treatment.

| S-EPMC5411684 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data