Scaffold repositioning of spiro-acridine derivatives as fungi chitinase inhibitor by target fishing and in vitro studies

Abstract

The concept of “one target, one drug, one disease” is not always true, as compounds with previously described therapeutic applications can be useful to treat other maladies. For example, acridine derivatives have several potential therapeutic applications. In this way, identifying new potential targets for available drugs is crucial for the rational management of diseases. Computational methodologies are interesting tools in this field, as they use rational and direct methods. Thus, this study focused on identifying other rational targets for acridine derivatives by employing inverse virtual screening (IVS). This analysis revealed that chitinase enzymes can be potential targets for these compounds. Subsequently, we coupled molecular docking consensus analysis to screen the best chitinase inhibitor among acridine derivatives. We observed that 3 compounds displayed potential enhanced activity as fungal chitinase inhibitors, showing that compound 5 is the most active molecule, with an IC50 of 0.6 ng/µL. In addition, this compound demonstrated a good interaction with the active site of chitinases from Aspergillus fumigatus and Trichoderma harzianum. Additionally, molecular dynamics and free energy demonstrated complex stability for compound 5. Therefore, this study recommends IVS as a powerful tool for drug development. The potential applications are highlighted as this is the first report of spiro-acridine derivatives acting as chitinase inhibitors that can be potentially used as antifungal and antibacterial candidates.

Design of Protease-Responsive Antifungal Liposomal Formulation Decorated with a Lipid-Modified Chitin-Binding Domain

“…Chitin, a complex polysaccharide composed of β-1,4-N-acetylglucosamine monomers, is an essential component of fungal cell walls and a promising antifungal drug target. Chitinase, which generally consists of a catalytic domain and a chitin-binding domain, can be used to break down chitin into its oligomers and/or monomers, thereby destroying the fungal cell wall structure and ultimately inhibiting cell growth [30]. Furthermore, chitin is also absent in humans, thus making antifungal drugs that target chitin an ideal strategy.…”

Leveraging binding pose metadynamics to optimise target fishing predictions for three diverse ligands and their true targets

“…Theoretically, the same principle should apply to the binding of a ligand to its true target, whose protein-ligand complex should demonstrate superior stability compared to other predicted targets. While several other studies have previously utilized MD-based methods as a follow-up to target fishing predictions (de Oliveira Viana et al, 2023;Del Favero et al, 2022;Wang, Shen, et al, 2017), these studies have typically aimed to validate target fishing predictions for a ligand with unknown targets, rather than systematically evaluate the ability of such methods to refine initial predictions. Therefore, in this study we aim to evaluate the ability of BPMD and its related scoring function to improve the predictions of a common target fishing algorithm across three diverse ligands and their six true targets.…”