title: Isolation, characterization and antifungal docking studies of wortmannin isolated from Penicillium radicum.
abstract: During the search for a potent antifungal drug, a cell-permeable metabolite was isolated from a soil isolate taxonomically identified as Penicillium radicum. The strain was found to be a potent antifungal agent. Production conditions of the active compound were optimized and the active compound was isolated, purified, characterized and identified as a phosphoinositide 3-kinase (PI3K) inhibitor, commonly known as wortmannin (Wtmn). This is very first time we are reporting the production of Wtmn from P. radicum. In addition to its previously discovered anticancer properties, the broad spectrum antifungal property of Wtmn was re-confirmed using various fungal strains. Virtual screening was performed through molecular docking studies against potential antifungal targets, and it was found that Wtmn was predicted to impede the actions of these targets more efficiently than known antifungal compounds such as voriconazole and nikkomycin i.e. 1) mevalonate-5-diphosphate decarboxylase (1FI4), responsible for sterol/isoprenoid biosynthesis; 2) exocyst complex component SEC3 (3A58) where Rho- and phosphoinositide-dependent localization is present and 3) Kre2p/Mnt1p a Golgi alpha1,2-mannosyltransferase (1S4N) involved in the biosynthesis of yeast cell wall glycoproteins). We conclude that Wtmn produced from P. radicum is a promising lead compound which could be potentially used as an efficient antifungal drug in the near future after appropriate structural modifications to reduce toxicity and improve stability.
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow-226031, Uttar Pradesh, India.
authors.forename: Vineeta
authors.initials: V
authors.lastname: Singh
authors.affiliation: Fermentation Technology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow-226031, Uttar Pradesh, India.
authors.forename: Vandana
authors.initials: V
authors.lastname: Praveen
authors.affiliation: Division of Organic Chemistry, CSIR - National Chemical Laboratory, Pune- 411008, Maharashtra, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Tripathi
authors.affiliation: 1] Department of Biosciences, Jamia Millia Islamia (A Central University), New Delhi-110025, India [2] Centre for Drug Research, Faculty of Pharmacy, Viikki Biocentre-2, FI-00014, University of Helsinki, Helsinki, Finland.
authors.forename: Shafiul
authors.initials: S
authors.lastname: Haque
authors.affiliation: Department of Biotechnology, TERI University, New Delhi-110070, India.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Somvanshi
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow-226031, Uttar Pradesh, India.
authors.forename: S B
authors.initials: SB
authors.lastname: Katti
authors.affiliation: Fermentation Technology Division, CSIR-Central Drug Research Institute, Sitapur Road, Lucknow-226031, Uttar Pradesh, India.
authors.forename: C K M
authors.initials: CK
authors.lastname: Tripathi
mesh_terms: D000730:Androstadienes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism; D005658:Fungi / Q000187:drug effects; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D010407:Penicillium / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010802:Phylogeny; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000935:Antifungal Agents; D005656:Fungal Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077191:Wortmannin