NDLI: How Nutlin-3 disrupts the MDM2–p53 interaction: a theoretical investigation

Content Provider	Springer Nature Link
Author	Abdur Rauf, Shah Md. Takaba, Hiromitsu Carpio, Carlos A. Miyamoto, Akira
Copyright Year	2013
Abstract	The tumor suppressor protein p53 is inhibited while mouse double minute 2 (MDM2) protein binds on its transactivation domain. Overexpression of MDM2 impairs p53 function and are observed in many human tumors. Disruption of MDM2–p53 interaction leads to increased p53 level and restores p53 transcriptional activity. Restoration of p53 activity through inhibiting the interaction between p53 and MDM2 represents a promising approach for cancer therapy. A number of small-molecule p53–MDM2 binding inhibitors have been developed during the past several years. Nutlin-3 has shown a potent and selective small-molecule MDM2 antagonist which has a considerable promise in pre-clinical studies. In this study we investigated theoretically the interaction of Nutlin-3 with MDM2 at atomistic level, and compared to the interaction of p53 with MDM2 to explore the molecular basis of inhibition. In MDM2–p53 model, there are three hydrogen bonding interactions between MDM2 and p53. The lengths of the hydrogen bonds are found to be 2.45, 2.46, and 1.89 Å whereas interaction energies are −3.82, −3.76, and −5.32 kcal/mol, respectively. The sum of three hydrogen bonding energy is −12.90 kcal/mol. On the other hand, in MDM2–Nutlin-3 model there are four hydrogen bond interactions between MDM2 and Nutlin-3. The bond lengths are found to be 2.29, 1.77, 2.48, and 2.39 Å whereas interaction energies are −4.21, −6.63, −3.65, and −3.63 kcal/mol, respectively. The sum of three hydrogen bonding energy is −18.12 kcal/mol. From the comparison between two models, it is revealed that MDM2–Nutlin3 model has four hydrogen bonds whereas MDM2–p53 model has three hydrogen bonds. The interaction energy in MDM2–Nutlin-3 is relatively more stable than MDM2–p53 interaction. Due to stronger hydrogen bond interaction with higher interaction energy, Nutlin-3 blocks the p53-binding pocket of MDM2 and thus disrupts the MDM2–p53 interaction and helps to activate p53 pathway of apoptosis.
Starting Page	1998
Ending Page	2006
Page Count	9
File Format	PDF
ISSN	10542523
Journal	Medicinal Chemistry Research
Volume Number	23
Issue Number	4
e-ISSN	15548120
Language	English
Publisher	Springer US
Publisher Date	2013-09-28
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	MDM2–Nutlin3 interaction p53 Hydrogen bonds MIAX UA-QCMD Pharmacology/Toxicology Biochemistry Cell Biology
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology, Toxicology and Pharmaceutics

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Combination therapy with p53–MDM2 binding inhibitors for malignancies

Quercetin and taxifolin completely break MDM2–p53 association: molecular dynamics simulation study

Inhibitors of the p53-Mdm2 interaction increase programmed cell death and produce abnormal phenotypes in the placozoon Trichoplax adhaerens (F.E. Schulze)

Letter to the Editor: Quercetin and taxifolin completely break MDM2-p53 association: molecular dynamics simulation study by S. Verma, A. Singh, A. Mishra. Med Chem Res 2013, 22(6) 2778–2787

The MDM2 ligand Nutlin-3 differentially alters expression of the immune blockade receptors PD-L1 and CD276

Restoration of p53–DNA interaction loss upon R273H mutation by CP-31398: an ultra accelerated quantum chemical molecular dynamics approach

Invited abstracts

Oral Presentation Abstracts

Nicotine and Pain

How Nutlin-3 disrupts the MDM2–p53 interaction: a theoretical investigation

Similar Documents

Combination therapy with p53–MDM2 binding inhibitors for malignancies

Quercetin and taxifolin completely break MDM2–p53 association: molecular dynamics simulation study

Inhibitors of the p53-Mdm2 interaction increase programmed cell death and produce abnormal phenotypes in the placozoon Trichoplax adhaerens (F.E. Schulze)

Letter to the Editor: Quercetin and taxifolin completely break MDM2-p53 association: molecular dynamics simulation study by S. Verma, A. Singh, A. Mishra. Med Chem Res 2013, 22(6) 2778–2787

The MDM2 ligand Nutlin-3 differentially alters expression of the immune blockade receptors PD-L1 and CD276

Restoration of p53–DNA interaction loss upon R273H mutation by CP-31398: an ultra accelerated quantum chemical molecular dynamics approach

Invited abstracts

Oral Presentation Abstracts

Nicotine and Pain

How Nutlin-3 disrupts the MDM2–p53 interaction: a theoretical investigation