Novel Inhibitors of Trihydroxynaphthalene Reductase with Antifungal Activity Identified by Ligand-Based and Structure-Based Virtual Screening

Abstract

Curvularia lunata is a dark pigmented fungus that is the causative agent of several diseases in plants and in both immunodeficient and immunocompetent patients. 1,8-Dihydroxynaphthalene-melanin is found in the cell wall of C. lunata and is believed to be the important virulence factor of dematiaceous fungi. Trihydroxynaphthalene reductase is an enzyme of the 1,8-dihydroxynaphthalene-melanin biosynthetic pathway, and it thus represents an emerging target for the development of novel fungicides and antimycotics. In the present study, we describe novel inhibitors of trihydroxynaphthalene reductase from C. lunata. These inhibitors were identified by ligand-based three-dimensional similarity searching and docking to a homology-built model and by subsequent biochemical and antifungal evaluation. Discovery of competitive inhibitors with K(i) values in low micromolar and even nanomolar concentration range proves the aplicability of homology-built model of 3HNR for hit finding by virtual screening methods.

Structure-Based Virtual Screening for Drug Discovery: a Problem-Centric Review

“…For example, in a recent attempt to identify novel inhibitors of trihydroxynaphthalene reductase (3HNR) (53), the authors first overlaid the known 3HNR inhibitors and then constructed a pharmacophore model that consists of several key interaction points within the active site: H-bonds with Ser149, Tyr163, Met200, and Tyr201 and π-stacking with Tyr208. In accordance to these interactions, the docking experiment was conducted in such a way that it only considered docking solutions that predicted π-stacking with Tyr208 and an optional H-bond with Ser149.…”

A flavoprotein supports cell wall properties in the necrotrophic fungus Alternaria brassicicola

“…Detailed insight into the DHN-melanin synthesis process in fungi is important primarily because this pigment contributes to virulence in several human and plant pathogenic fungi. Enzymes involved in the DHN-melanin biosynthetic pathway are thus emerging targets for the development of selective fungicides since this pigment is not synthesized in host organisms [ 40 ]. Biological control strategies have also been envisaged to limit the accumulation and persistence of plant pathogens by degrading their melanin content or inhibiting its production [ 41 ].…”

Advances in the Development of Shape Similarity Methods and Their Application in Drug Discovery

“…As shape matching calculations are comparatively faster than structure based virtual screening methods, it is generally used during initials steps of a hierarchical virtual screening protocol. This hierarchical combination of shape similarity with molecular docking has been successfully employed in the discovery of type II dehydroquinase inhibitors (Ballester et al, 2012 ) and that of MDM2 inhibitors (Houston et al, 2015 ), 11β-hydroxysteroid dehydrogenase 1 inhibitors (Xia et al, 2011 ), PPARγ partial agonists (Vidović et al, 2011 ), inhibitors of chemokine receptor 5 (CCR5)-N terminus binding to gp120 protein (Acharya et al, 2011 ), Grb7-based antitumor agents (Ambaye et al, 2013 ), fungal trihydroxynaphthalene reductase inhibitors (Brunskole Švegelj et al, 2011 ), non-steroidal FXR ligands (Fu et al, 2012 ; Wang et al, 2015 ), novel SIRT3 scaffolds (Salo et al, 2013 ), protein kinase CK2 inhibitors (Sun et al, 2013 ), SUMO conjugating enzyme inhibitors (Kumar et al, 2014a ), and chemokine receptor type 4 inhibitors (Das et al, 2015 ). Combination of shape similarity methods with structure-based methods such as docking provide several advantages.…”