Structural Insight of NICD-MAML Interactions: Virtual Screening, Docking and Molecular Dynamics Study for Identification of Potential Inhibitor

Author(s): Noopur Sinha, Saikat Chowdhury, Ram Rup Sarkar

Journal Name: Letters in Drug Design & Discovery

Volume 13 , Issue 4 , 2016

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Abstract:

Activation of Notch signalling pathway is triggered by binding of NICD to transcription factor CSL and transcriptional co-activator MAML, which involves in various biological functions as well as progression of diseases. Recent prediction shows suppression of cancer causing genes of this pathway through inhibition of NICD-MAML interaction. Through virtual screening against “NCI Diversity 3” of Zinc database, we identified a potential inhibitor “ZINC01690699” (1-N,4-N-bis[3-(1Hbenzimidazol- 2-yl)phenyl]benzene-1,4-dicarboxamide; 1-N,4-dicarboxamide) possessing highest binding affinity to block the two distinct Binding Sites of NICD to inhibit NICD-MAML interaction and also found the most imperative and essential Binding Site (Site I). Inhibition of this interaction caused by binding of ZINC01690699 is validated by protein-protein docking and the prolonged binding as well as stability of NICD-Inhibitor complex is supported by molecular dynamics simulation. The study not only identifies the best inhibitor but also proposes a potential drug for the treatment of cancers.

Keywords: Notch signalling, NICD, MAML, potential inhibitor, free energy of binding, ZINC01690699.

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Article Details

VOLUME: 13
ISSUE: 4
Year: 2016
Page: [301 - 313]
Pages: 13
DOI: 10.2174/1570180812666150819003634
Price: $65

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