title: Benzoic acid derivatives with improved antifungal activity: Design, synthesis, structure-activity relationship (SAR) and CYP53 docking studies.
abstract: Previously, we identified CYP53 as a fungal-specific target of natural phenolic antifungal compounds and discovered several inhibitors with antifungal properties. In this study, we performed similarity-based virtual screening and synthesis to obtain benzoic acid-derived compounds and assessed their antifungal activity against Cochliobolus lunatus, Aspergillus niger and Pleurotus ostreatus. In addition, we generated structural models of CYP53 enzyme and used them in docking trials with 40 selected compounds. Finally, we explored CYP53-ligand interactions and identified structural elements conferring increased antifungal activity to facilitate the development of potential new antifungal agents that specifically target CYP53 enzymes of animal and plant pathogenic fungi.
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia. Electronic address: sabina.berne@mf.uni-lj.si.
authors.forename: Sabina
authors.initials: S
authors.lastname: Berne
authors.affiliation: Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia; UCD Conway Institute, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Lidija
authors.initials: L
authors.lastname: Kovačič
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Matej
authors.initials: M
authors.lastname: Sova
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
authors.forename: Nada
authors.initials: N
authors.lastname: Kraševec
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.affiliation: Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia; Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia.
authors.forename: Igor
authors.initials: I
authors.lastname: Križaj
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia. Electronic address: radovan.komel@mf.uni-lj.si.
authors.forename: Radovan
authors.initials: R
authors.lastname: Komel
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001203:Ascomycota / Q000187:drug effects; D001234:Aspergillus niger / Q000187:drug effects; D019817:Benzoic Acid / Q000737:chemistry*; D003580:Cytochromes / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy / Q000379:methods; D020076:Pleurotus / Q000187:drug effects; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D003580:Cytochromes; D005656:Fungal Proteins; D019817:Benzoic Acid
keywords: Antifungal activity; Benzoic acid; CYP53; Cytochrome P450; Molecular docking; Molecular modeling; SAR