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conferenceseries
.com
Volume 10, Issue 8 (Suppl)
J Proteomics Bioinform, an open access journal
ISSN: 0974-276X
Structural Biology 2017
September 18-20, 2017
9
th
International Conference on
Structural Biology
September 18-20, 2017 Zurich, Switzerland
Ameena M Ali et al., J Proteomics Bioinform 2017, 10:8(Suppl)
DOI: 10.4172/0974-276X-C1-0101
Screening for P53-MDM2 small molecule inhibitors: Cancer therapeutic target
Ameena M Ali
1
, Jack Atmaj
1
, Matthew R Groves
1
, Neochoritis, C G
2
, Daniel G Rivera
3
, Tad Holak
4
and
Alexander Dömling
1
1
Faculty of Science and Engineering, Drug Design Department, Groningen University, Netherlands
2
Telesispharma B.V, Groningen, Netherlands
3
Faculty of Chemistry, University of Havana, Cuba
4
Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Poland
Statement of the Problem:
p53 is the key tumor suppressor protein and the guardian of the genome. Mutation or deletion in
TP53
gene, which encode p53 protein, is the main trigger for >50% of human cancer due to the protein’s central role in cell
cycle checkpoints. This lead to over-expression of MDM2 and down regulation of mutated P53 in parallel. MDM2 (Mouse
Double Minute 2, also named Hdm2 in humans) is an oncoprotein that negatively regulates the apoptotic function of p53
via
transactivation inhibition in two manners: either by direct protein- protein interaction (PPI) or by targeting P53 to proteasome
degradation through its
E3
ligase
activity. The purpose of this study is to design and optimize small molecules that block the
PPI between P53 and MDM2 as a novel non-genotoxic target for anticancer drugs.
Methodology &Theoretical Orientation:
MDM2 protein was first expressed in inclusion bodies, refolded and then purified.
Highly pure MDM2 was used for optimized compounds screening and analyzing their binding to MDM2. To achieve this
goal protein was co-crystallized with the optimized compounds and their binding modes will be characterized by X-ray
crystallography. Moreover, the binding kinetics of the same compounds was estimated using fluorescence polarization (FP)
and microscale thermophoresis (MST).
Findings:
Some of the screened compounds showed a high binding affinity toward MDM2 with K
d
values down to nano-molar
values.
Conclusion & Significance:
We anticipate that our studies will result in further improvements in the affinity of the inhibitors
targeting the MDM2: p53 interaction.
Biography
Ameena M Ali is a PhD student in Drug Design Department at Groningen University since 2015. She conducts her structural biology and crystallography research
under the supervision of Prof. Alexander Dömling and Dr. Matthew Groves. She became the main Researcher in MDM2: P53 (PPI) inhibitor discovery and screening
in 2016. She was honored with a Master’s degree in Medical Biotechnology from the Arabian Gulf University, Kingdom of Bahrain in 2012, while she received her
Bachelor’s degree in 2003 from Qatar University in Biological and Environmental Sciences with excellence. Most of her research work focused on diseases and
treatment strategy development for critical diseases such as, point mutations in
LDL
gene, Diabetes Mellitus and Cancer.
a.ali@rug.nlFigure:1
MDM2 Hydrophobic Pocket (grey)
interacting with P53 peptide (red) via three hot
spots amino acids (Leu26, Phe19, Trp23) in PPI
manner.