Fullerene quinazolinone conjugates targeting Mycobacterium tuberculosis: a combined molecular docking,QSAR, and ONIOM approach

Fullerene and its derivatives may bind to biological molecules, causing inhibitory effects. In this context, investigations of interactions of fullerene-based conjugates with proteins are of general interest. Particularly, fullerene and its derivatives demonstrate antibacterial properties; and one of the potential targets for drug design and health therapy is the inhibition of 6-oxopurine phosphoribosyltransferase in Mycobacterium tuberculosis (PDB code: 4RHY). In this article, the binding interactions between a series of quinazoline-4(3H)-ones and their fullerene derivatives with the target transferase were computationally investigated. Initially, we developed predictive quantitative structure-activity relationships (QSAR) models. Next, we introduced a simplified calculation schema that allows to evaluate relative binding affinities and to reveal specific mechanisms of action. For this purpose, the molecular docking approach was utilized to identify the native poses of the 18 transferase inhibitors. The binding pocket of the target protein was isolated and semi-empirical, and hybrid ONIOM scoring functions at different levels of theory were used to treat the ligands and the isolated binding pocket. The agreement within the calculated binding-free energies trends, as well as the agreement with the experimental data, suggests that the developed calculation schema can be used to estimate relative binding affinities towards 4RH. The combination of quantum-chemical models and QSAR models could be applied for future design of new selective inhibitors.