Watermelon: setup and validation of an in silico fragment-based approach

Abstract

We present a new computational approach, named Watermelon, designed for the development of pharmacophore models based on receptor structures. The methodology involves the sampling of potential hotspots for ligand interactions within a protein target’s binding site, utilising molecular fragments as probes. By employing docking and molecular dynamics (MD) simulations, the most significant interactions formed by these probes within distinct regions of the binding site are identified. These interactions are subsequently transformed into pharmacophore features that delineates key anchoring sites for potential ligands. The reliability of the approach was experimentally validated using the monoacylglycerol lipase (MAGL) enzyme. The generated pharmacophore model captured features representing ligand-MAGL interactions observed in various X-ray co-crystal structures and was employed to screen a database of commercially available compounds, in combination with consensus docking and MD simulations. The screening successfully identified two new MAGL inhibitors with micromolar potency, thus confirming the reliability of the Watermelon approach.

Keywords:

• Pharmacophore model
• drug design
• virtual screening

Authors contributions

Conceptualisation, M.M., T.T., and G.P.; methodology, M.D.S. and S.G.; validation, M.D.S., S.G., F.G., and L.P.; formal analysis, M.D.S., S.G., C.G., F.G., M.M., and A.G.; resources, T.T. and M.M.; data curation, M.D.S., S.G., C.G. and A.G.; writing-original draft preparation, M.D.S., S.G., T.T., and G.P.; supervision, T.T.; funding acquisition, T.T., and M.M. All authors have read and agreed to the published version of the manuscript. All authors agree to be accountable for all aspects of the work.

Disclosure statement

No potential competing interest was reported by all authors except TT. Tiziano Tuccinardi is a member of the Editorial Board of the Journal of Enzyme Inhibition and Medicinal Chemistry. He was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Data availability statement

The data that support the findings of this study are available from the corresponding author, [TT], upon reasonable request.

Additional information

Funding

This work was supported by the Italian Ministry of Health under Grant [Ricerca Finalizzata 2016 – NET-2016–02363765].