Title:Structural Insight of NICD-MAML Interactions: Virtual Screening, Docking and Molecular Dynamics Study for Identification of Potential Inhibitor
Volume: 13
Issue: 4
Author(s): Noopur Sinha, Saikat Chowdhury and Ram Rup Sarkar
Affiliation:
Keywords:
Notch signalling, NICD, MAML, potential inhibitor, free energy of binding, ZINC01690699.
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.
