Open AccessInhibitors of the Cdc34 acidic loop: A computational investigation integrating molecular dynamics, virtual screening and docking approaches
Author(s) -
Arrigoni Alberto,
Bertini Luca,
De Gioia Luca,
Papaleo Elena
Publication year - 2014
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1016/j.fob.2014.04.011
Subject(s) - virtual screening , pharmacophore , molecular dynamics , docking (animal) , hydrogen bond , chemistry , ubiquitin , molecular model , stereochemistry , combinatorial chemistry , molecule , computational biology , biochemistry , biophysics , computational chemistry , biology , organic chemistry , medicine , nursing , gene
Here, we carried out a computational study based on molecular dynamics, virtual screening and docking to identify potential inhibitory compounds of Cdc34, modulating the acidic loop conformation. The molecules identified in this study have been designed to act as molecular hinges that can bind the acidic loop in its closed conformation, thus inhibiting the Cdc34‐mediated ubiquitination cascade at the ubiquitin‐charging step. In particular, we proposed a pharmacophore model featuring two amino groups in the central part of the model and two lateral aromatic chains, which respectively establish electrostatic interactions with the acidic loop (Asp 108 and Glu 109) and a hydrogen bond with Ser 139, which is one of the key residues for Cdc34 activity.