Discovery of Potential Inhibitors for Trihydroxynaphthalene Reductase (۳HNR) by virtual screening

Background and Aim : Curvularia lunata is a dark pigmented fungus that is the causative agent of several diseases in plants and humans like that immunodeficient, eyes infection and allergic disease.۱,۸-Dihydroxynaphthalene-melanin (DHN) was produced by Trihydroxynaphthalene Reductase (۳HNR) enzyme during the biosynthetic pathway in the cell wall of C. lunata which cause disease. The aim of this study is to discover novel inhibitors for the ۳HNR enzyme to prevent the production of DHN by using in silico virtual screening method.Methods : All molecular modeling was carried out using the small-Molecular Drug Discovery Suite ۲۰۱۵-۲ (Schrodinger, LLC, New York, NY, ۲۰۱۶). proteins were obtained from a protein data bank (PDB: ۱DOH). The protein preparation and prime application were performed to minimize the protein strains state. The High Throughput Virtual Screening (HTVS) protocol was used as a method for discovering novel ۳HNR inhibitors. The molecular modeling was subjected to using the Glide application using extra precision (XP) protocol. Over ۶۰۰۰ natural products downloaded from ZINC۱۵ were prepared with Ligprep application; The ADME properties of all compounds were analyzed and a final selection was made based on the Lipinski rule of five. Results : The results of molecular docking showed that ZINC۹۵۹۰۳۴۲, ZINC۱۴۸۱۴۶۱۲ (isochromen-۱-one) and ZINC۳۱۱۶۶ (epilupinine) with docking scores -۹.۶۵۶, -۹.۴۸۷ and -۹.۳۲۴ kcal/mol, respectively are good candidates. These compounds formed a hydrogen bond with SER۱۶۴ and TYR۱۷۸, had high affinity to receptor with the highest inhibitory activity on ۱-DOH receptor.Conclusion : Our finding shows that these compounds on inhibitory potential ۳HNR enzyme and controlling C. lunata fungi in humans and plants. The isochromen-۱-one is coumarin derivatives, previously reported to have activity against Candida albicans species and inhibited sterol ۱۴-alpha demethylase enzyme.

Keywords:

Curvularia lunata , trihydroxynaphthalene reductase , Molecular Docking , Natural product