Identification of potential biological targets of oxindole scaffolds via in silico repositioning strategies

Tinivella, Annachiara; Pinzi, Luca; Gambacorta, Guido; Baxendale, Ian; Rastelli, Giulio

Abstract

Background: Drug repurposing is an alternative strategy to traditional drug discovery that aims at predicting new uses for already existing drugs or clinical candidates. Drug repurposing has many advantages over traditional drug development, such as reduced attrition rates, time and costs. This is especially the case considering that most drugs investigated for repurposing have already been assessed for their safety in clinical trials. Repurposing campaigns can also be designed for libraries of already synthesized molecules at different levels of biological experimentation, from null to in vitro and in vivo. Such an extension of the “repurposing” concept is expected to provide significant advantages for the identification of novel drugs, as the synthetic accessibility of the desired compounds is often one of the limiting factors in the traditional drug discovery pipeline. Methods: In this work, we performed a computational repurposing campaign on a library of previously synthesized oxindole-based compounds, in order to identify potential new targets for this versatile scaffold. To this aim, ligand-based approaches were firstly applied to evaluate the similarity degree of the investigated compound library, with respect to ligands extracted from the DrugBank, Protein Data Bank (PDB) and ChEMBL databases. In particular, the 2D fingerprint-based and 3D shape-based similarity profiles were evaluated and compared for the oxindole derivates. Results: The analyses predicted a set of potential candidate targets for repurposing, some of them emerging by consensus of different computational analyses. One of the identified targets, i.e., the vascular endothelial growth factor receptor 2 (VEGFR-2) kinase, was further investigated by means of docking calculations, followed by biological testing of one candidate. Conclusions: While the compound did not show potent inhibitory activity towards VEGFR-2, the study highlighted several other possibilities of therapeutically relevant targets that may be worth of consideration for drug repurposing.

Citation

Tinivella, A., Pinzi, L., Gambacorta, G., Baxendale, I., & Rastelli, G. (2022). Identification of potential biological targets of oxindole scaffolds via in silico repositioning strategies. F1000Research, 11, https://doi.org/10.12688/f1000research.109017.2

• Journal Article Type: Article
• Online Publication Date: Mar 23, 2022
• Publication Date: 2022
• Deposit Date: Apr 3, 2023
• Publicly Available Date: Apr 3, 2023
• Journal: F1000Research
• Electronic ISSN: 2046-1402
• Publisher: Taylor and Francis
• Peer Reviewed: Peer Reviewed
• Volume: 11
• DOI: https://doi.org/10.12688/f1000research.109017.2
• Public URL: https://durham-repository.worktribe.com/output/1177777