Target Protein Identification Using CSD-CrossMiner
August 30, 2023
This blog is based on a research paper published in the Journal of Heterocyclic Chemistry that focuses on optimizing an electrocatalytic method for the synthesis of spirobarbiturates and identifying medicinally relevant target proteins using CSD-CrossMiner.
What Are Spirobarbiturates?
Barbiturates are a class of compounds derived from barbituric acid that are widely used in medicinal chemistry as depressant drugs. Recently it has been shown that they also possess anti-AIDS and anti-cancer activity.
Spiro compounds are organic molecules of at least two molecular rings connected through only one atom. They are ideal compounds for target recognition thanks to their rigid systems with definite flexibility and specific orientation of the functional substituents.
Spirobarbiturates are compounds that combine the characteristics of barbiturates and spiro compounds. They are a specific type of heterocyclic spiro compounds which are obtained from a double functionalization at the C-5 position of barbituric acid.
Spirobarbiturates have received attention from the pharmaceutical community in the last decades for their biological properties, and are used today in numerous treatments for inflammatory, infectious, immunological, and malignant diseases.
The research group aimed to design an efficient electrocatalytic one-pot methodology to synthesize unsymmetric spirobarbiturates. The interactions between medicinally relevant proteins and the synthesized spirobarbiturates using molecular docking were then investigated.
Starting with the optimization of the electrochemical method, the scientists found that the best yields (62%-76%) for the synthesis of substituted unsymmetric spirobarbituric dihydrofurans were obtained when MeOH was used as a solvent, sodium bromide as a mediator, and 2.6 F/mol of electricity was passed.
After confirming with 1H, 13C NMR, IR spectroscopy, mass spectrometry and elemental analysis that the structures for the 12 substituted spirobarbituric dihydrofurans synthesized were the expected ones, focus was given to molecular docking studies.
Searching for a target protein for a newly synthesised family of compounds is not immediate. The group did not succeed in using the PASS-online service for this purpose, as an appropriate protein structure ideal for modelling was initially not found.
To further investigate the search for a target for spirobarbituric dihydrofuran compounds, the scientists employed CSD-CrossMiner. As part of the CSD-Discovery suite, CSD-CrossMiner performs scaffold searches by interrogating several structural databases.
Specifying the parameters of ligands or proteins while performing the search query reduces the outputs of structures obtained from the search. This led to the identification of a suitable protein from the scaffold search performed: the human aldose reductase complexed with the ligand naphtho[1,2-d]isothiazole (PDB code: 2NVD).
Aldose reductase is a catalyst for the reduction of glucose into sorbitol that is present in all target tissues with diabetic complications. Inhibitors of this enzyme, including naphtho[1,2-d]isothiazole, are used for the treatment of diabetic peripheral neuropathy.
The group performed molecular docking to predict the interactions between aldose reductase and the synthesized spirobarbituric dihydrofuran compounds. Two of the newly synthesized compounds revealed to be the most promising candidates, with energies of interaction that were comparable with the ones of known inhibitors of aldose reductase.
This work showed how the use of the scaffold search in CSD-CrossMiner allowed and simplified the search for a target protein for spirobarbituric dihydrofuran compounds. The study of the protein–ligand interactions proved the efficiency of the search performed, revealing two compounds from the newly synthesized ones that exhibited properties similar to the ones of known inhibitors of aldose reductase.
Drug Development (42)
Drug Discovery (56)