Application of the fragment molecular orbital method to discover novel natural products for prion disease

Jiwon Choi, Hyo Jin Kim, Xuemei Jin, Hocheol Lim, Songmi Kim, In Soon Roh, Hae Eun Kang, Kyoung Tai No, Hyun Joo Sohn

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Conformational conversion of the normal cellular isoform of the prion protein PrP C into an infectious isoform PrP Sc causes pathogenesis in prion diseases. To date, numerous antiprion compounds have been developed to block this conversion and to detect the molecular mechanisms of prion inhibition using several computational studies. Thus far, no suitable drug has been identified for clinical use. For these reasons, more accurate and predictive approaches to identify novel compounds with antiprion effects are required. Here, we have applied an in silico approach that integrates our previously described pharmacophore model and fragment molecular orbital (FMO) calculations, enabling the ab initio calculation of protein-ligand complexes. The FMO-based virtual screening suggested that two natural products with antiprion activity exhibited good binding interactions, with hotspot residues within the PrP C binding site, and effectively reduced PrP Sc levels in a standard scrapie cell assay. Overall, the outcome of this study will be used as a promising strategy to discover antiprion compounds. Furthermore, the SAR-by-FMO approach can provide extremely powerful tools in quickly establishing virtual SAR to prioritise compounds for synthesis in further studies.

Original languageEnglish
Article number13063
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Prions
Molecular orbitals
Biological Products
Protein Isoforms
Orbital calculations
Assays
Screening
Binding Sites
Ligands
Pharmaceutical Preparations
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Choi, Jiwon ; Kim, Hyo Jin ; Jin, Xuemei ; Lim, Hocheol ; Kim, Songmi ; Roh, In Soon ; Kang, Hae Eun ; No, Kyoung Tai ; Sohn, Hyun Joo. / Application of the fragment molecular orbital method to discover novel natural products for prion disease. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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Application of the fragment molecular orbital method to discover novel natural products for prion disease. / Choi, Jiwon; Kim, Hyo Jin; Jin, Xuemei; Lim, Hocheol; Kim, Songmi; Roh, In Soon; Kang, Hae Eun; No, Kyoung Tai; Sohn, Hyun Joo.

In: Scientific reports, Vol. 8, No. 1, 13063, 01.12.2018.

Research output: Contribution to journalArticle

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