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Comparing Drug Images and Repurposing Drugs with BioGPS and FLAPdock: The Thymidylate Synthase Case
Author(s) -
Siragusa Lydia,
Luciani Rosaria,
Borsari Chiara,
Ferrari Stefania,
Costi Maria Paola,
Cruciani Gabriele,
Spyrakis Francesca
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600121
Subject(s) - drug repositioning , protein data bank (rcsb pdb) , thymidylate synthase , repurposing , drug discovery , chemistry , protein data bank , computational biology , drugbank , virtual screening , target protein , biochemistry , in silico , drug , biology , pharmacology , protein structure , ecology , fluorouracil , genetics , chemotherapy , gene
Repurposing and repositioning drugs has become a frequently pursued and successful strategy in the current era, as new chemical entities are increasingly difficult to find and get approved. Herein we report an integrated BioGPS/FLAPdock pipeline for rapid and effective off‐target identification and drug repurposing. Our method is based on the structural and chemical properties of protein binding sites, that is, the ligand image, encoded in the GRID molecular interaction fields (MIFs). Protein similarity is disclosed through the BioGPS algorithm by measuring the pockets’ overlap according to which pockets are clustered. Co‐crystallized and known ligands can be cross‐docked among similar targets, selected for subsequent in vitro binding experiments, and possibly improved for inhibitory potency. We used human thymidylate synthase (TS) as a test case and searched the entire RCSB Protein Data Bank (PDB) for similar target pockets. We chose casein kinase IIα as a control and tested a series of its inhibitors against the TS template. Ellagic acid and apigenin were identified as TS inhibitors, and various flavonoids were selected and synthesized in a second‐round selection. The compounds were demonstrated to be active in the low‐micromolar range.