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

Scientific Reports
Jiwon ChoiHyun-Joo Sohn

Abstract

Conformational conversion of the normal cellular isoform of the prion protein PrPC into an infectious isoform PrPSc 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 PrPC binding site, and effectively reduced PrPSc 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...Continue Reading

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Citations

Jun 13, 2019·Physical Chemistry Chemical Physics : PCCP·Hiroya Nakata, Dmitri G Fedorov
Jul 22, 2019·The Journal of Chemical Physics·Kuan-Yu LiuJohn M Herbert
Oct 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Vladimir I MuronetzMatej Sova
Dec 17, 2019·Journal of Chemical Theory and Computation·Danil S KaliakinLyudmila V Slipchenko
Aug 29, 2019·Journal of Chemical Theory and Computation·Dmitri G Fedorov
Feb 26, 2020·Journal of Chemical Theory and Computation·Alexander HeifetzAndrea Townsend-Nicholson

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Methods Mentioned

BETA
NMR
X-ray
electrophoresis
ELISA

Software Mentioned

BIOVIA Discovery
PyMOL
Schrödinger
CDOCKER
Maestro
BIOVIA
General Atomic and Molecular Electronic Structure System ( GAM...
RESPA
BIOVIA Discovery Studio
Desmond

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