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Current Chemical Biology

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ISSN (Print): 2212-7968
ISSN (Online): 1872-3136

Research Article

Computational Investigation on the MDM2-Idasanutlin Interaction Using the Potential of Mean Force Method

Author(s): Pundarikaksha Das and Venkata Satish Kumar Mattaparthi*

Volume 15, Issue 3, 2021

Published on: 16 July, 2021

Page: [262 - 270] Pages: 9

DOI: 10.2174/2212796815666210716151211

Price: $65

Abstract

Background: The Murine Double Minute 2 (MDM2) protein is a well-studied primary negative regulator of the tumor suppressor p53 molecule. Therefore, nowadays many research studies have focused on the inhibition of MDM2 with potent inhibitors. Idasanutlin (RG7388) is a well-studied small molecule, the antagonist of MDM2 with potential antineoplastic activity. Nevertheless, the highly significant information pertaining to the free energy profile, intermediates, and the association of receptor and ligand components in the MDM2-idasanutlin complex remains unclear.

Objective: To study the free energy profile of the MDM2-idasanutlin complex in terms of the Potential of Mean Force (PMF) method.

Methods: We have used the PMF method coupled with umbrella sampling simulations to generate the free energy profile for the association of N-Terminal Domain (NTD) of MDM2 and idasanutlin along with a specific reaction coordinate for identifying transition states, intermediates as well as the relative stabilities of the endpoints. We also have determined the binding characteristics and interacting residues at the interface of the MDM2-idasanutlin complex from the Binding Free Energy (BFE) and Per Residue Energy Decomposition (PRED) analyses.

Results: The PMF minima for the MDM2-idasanutlin complex was observed at a center of mass (CoM) distance of separation of 11 Å with dissociation energy of 17.5 kcal mol-1. As a function of the distance of separation of MDM2 from idasanutlin, we also studied the conformational dynamics as well as stability of the NTD of MDM2. We found that there is indeed a high binding affinity between MDM2 and idasanutlin (ΔGbinding = -3.19 kcal mol-1). We found that in MDM2, the residues MET54, VAL67, and LEU58 provide the highest energy input for the interaction between MDM2 and idasanutlin.

Conclusion: Our results in this study illustrate the significant structural and binding features of the MDM2-idasanutlin complex that may be useful in the development of potent inhibitors of MDM2.

Keywords: Potential of mean force, idasanutlin, binding free energy, per residue energy decomposition, MDM2, root mean square deviation.

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