title: Structure-based designing of sordarin derivative as potential fungicide with pan-fungal activity.
abstract: Fungal infections have become a significant problem for immunosuppressed patients. Sordarin, a promising fungicidal agent, inhibits fungal protein synthesis by impairing elongation factor-2 (eEF2) function. Intriguingly, despite high sequence similarity among eEF2s from different species, sordarin has been shown to inhibit translation specifically in certain fungi while unable to do so in some other fungal species (e.g. Candida parapsilosis and Candida lusitaniae). The sordarin binding site on eEF2 as well as its mechanism of action is known. In a previous study, we have detailed the interactions between sordarin and eEF2 cavities from different fungal species at the molecular level and predicted the probable cause of sordarin sensitivity. Guided by our previous analysis, we aimed for computer-aided designing of sordarin derivatives as potential fungicidal agents that still remain ineffective against human eEF2. We have performed structural knowledge-based designing of several sordarin derivatives and evaluated predicted interactions of those derivatives with the sordarin-binding cavities of different eEF2s, against which sordarin shows no inhibitory action. Our analyses identify an amino-pyrrole derivative as a good template for further designing of promising broad-spectrum antifungal agents. The drug likeness and ADMET prediction on this derivative also supports its suitability as a drug candidate.
authors.affiliation: Structural Biology & Bio-Informatics Division, Indian Institute of Chemical Biology (Council of Scientific & Industrial Research), 4, Raja S.C. Mullick Road, Kolkata 700 032, India.
authors.forename: Biprashekhar
authors.initials: B
authors.lastname: Chakraborty
authors.affiliation: The National Institute of Pharmaceutical Education and Research (NIPER), Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Nikunjkumar Vinodray
authors.initials: NV
authors.lastname: Sejpal
authors.affiliation: Structural Biology & Bio-Informatics Division, Indian Institute of Chemical Biology (Council of Scientific & Industrial Research), 4, Raja S.C. Mullick Road, Kolkata 700 032, India.
authors.forename: Pavan V
authors.initials: PV
authors.lastname: Payghan
authors.affiliation: Structural Biology & Bio-Informatics Division, Indian Institute of Chemical Biology (Council of Scientific & Industrial Research), 4, Raja S.C. Mullick Road, Kolkata 700 032, India.
authors.forename: Nanda
authors.initials: N
authors.lastname: Ghoshal
authors.affiliation: Structural Biology & Bio-Informatics Division, Indian Institute of Chemical Biology (Council of Scientific & Industrial Research), 4, Raja S.C. Mullick Road, Kolkata 700 032, India. Electronic address: jayati@iicb.res.in.
authors.forename: Jayati
authors.initials: J
authors.lastname: Sengupta
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000935:Antifungal Agents / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D000074429:Candida parapsilosis / Q000737:chemistry / Q000187:drug effects* / Q000472:pathogenicity; D015195:Drug Design; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D005659:Fungicides, Industrial / Q000737:chemistry; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D020652:Peptide Elongation Factor 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D005659:Fungicides, Industrial; D007192:Indenes; D020652:Peptide Elongation Factor 2; C003329:sordarin
keywords: Computational drug design; Elongation factor-2; Fungicide; Protein synthesis; Sordarin-binding pocket; Translation inhibition