Creating and virtually screening databases of fluorescently-labelled compounds for the discovery of target-specific molecular probes

Abstract

Our group has recently demonstrated that virtual screening is a useful technique for the identification of target-specific molecular probes. In this paper, we discuss some of our proof-of-concept results involving two biologically relevant target proteins, and report the development of a computational script to generate large databases of fluorescence-labelled compounds for computer-assisted molecular design. The virtual screening of a small library of 1,153 fluorescently-labelled compounds against two targets, and the experimental testing of selected hits reveal that this approach is efficient at identifying molecular probes, and that the screening of a labelled library is preferred over the screening of base compounds followed by conjugation of confirmed hits. The automated script for library generation explores the known reactivity of commercially available dyes, such as NHS-esters, to create large virtual databases of fluorescence-tagged small molecules that can be easily synthesized in a laboratory. A database of 14,862 compounds, each tagged with the ATTO680 fluorophore was generated with the automated script reported here. This library is available for downloading and it is suitable for virtual ligand screening aiming at the identification of target-specific fluorescent molecular probes.

N‐(2,4)‐dinitrophenyl‐L‐arginine Interacts with EphB4 and Functions as an EphB4 Kinase Modulator

“…The validation, screening and analog libraries were screened against the target structure using HierVLS, a hierarchical virtual screening protocol described in details elsewhere . This protocol reports force‐field‐based (FF) binding energies that take solvation into account for the best‐scoring protein–ligand complex generated for each ligand in the screening database.…”

Identifying potential selective fluorescent probes for cancer-associated protein carbonic anhydrase IX using a computational approach

“…Atto680 is a near-IR fluorophore that is commercially available in a reactive N-hydroxysuccinimidyl ester form [22]. The preparation of this database is described in a separate manuscript [23]. An additional subset of the MLSMR, was identified using PubChem BioAssay data.…”

“…Only the primary amine base moiety is shown. The Atto680 NHS ester is attached to the primary amine base moiety through an amide bond [23]. …”