Computational protocol: Identification of gefitinib off-targets using a structure-based systems biology approach; their validation with reverse docking and retrospective data mining

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Protocol publication

[…] The pockets of top 128 hits were estimated based on ligand proximity within a fixed distance threshold from the bound ligand. To extract the residues localized within threshold distance; “PockDrug-Server” (http://pockdrug.rpbs.univ-paris-diderot.fr) was used. The PDB files were uploaded on the server and “prox” method was selected to estimate the pocket using threshold distance at 4 Å. The ligand information in HET code was also given during prediction. [...] The potential off-targets-identified from MIF similarity search were further processed for binding analysis of gefitinib and previously characterized respective ligands. The Glide 6.9 ligand-receptor docking program (Schrödinger 10.4; Schrödinger Inc, USA) was used for docking of gefitinib to each off-target structure. The ligand library of gefitinib was prepared by LigPrep tool from Schrödinger program with OPLS-2005 force field. Receptor grid was generated in the vicinity of bound ligand of each identified-off target crystal structure using Glide-Receptor Grid generation tool with default parameters. Ligand docking was performed with extra precision (XP) Glide docking module. The binding energies of docking poses were calculated using MM-GBSA method (Prime, Schrödinger Inc, USA) with default parameters. […]

Pipeline specifications

Software tools PockDrug, Glide, LigPrep
Applications Drug design, Protein interaction analysis
Organisms Homo sapiens