ci0c00132_si_001.pdf (3.04 MB)
Evaluation of Free Energy Calculations for the Prioritization of Macrocycle Synthesis
journal contribution
posted on 2020-07-01, 11:40 authored by Janet L. Paulsen, Haoyu S. Yu, Dan Sindhikara, Lingle Wang, Todd Appleby, Armando G. Villaseñor, Uli Schmitz, Devleena ShivakumarA tremendous research and development
effort was exerted toward
combating chronic hepatitis C, ultimately leading to curative oral
treatments, all of which are targeting viral proteins. Despite the
advantage of numerous targets allowing for broad hepatitis C virus
(HCV) genotype coverage, the only host target inhibitors that advanced
into clinical development were Cyclosporin A based cyclophilin inhibitors.
While cyclosporin-based molecules typically require a fermentation
process, Gilead successfully pursued a fully synthetic, oral program
based on Sanglifehrin A. The drug discovery process, though greatly
helped by facile crystallography, was still hampered by the limitations
in the accuracy of predictive computational methods for prioritizing
compound ideas. Recent advances in accuracy and speed of free energy
perturbation (FEP) methods, however, are attractive for prioritizing
and derisking synthetically challenging molecules and potentially
could have had a significant impact on the speed of the development
of this program. Here in our simulated prospective study, the binding
free energies of 26 macrocyclic cyclophilin inhibitors were blindly
predicted using FEP+ to test this hypothesis. The predictions had
a low mean unsigned error (MUE) (1.1 kcal/mol) and accurately reproduced
many design decisions from the program, suggesting that FEP+ has the
potential to drive synthetic chemistry efforts by more accurately
ranking compounds with nonintuitive structure–activity relationships
(SARs).
History
Usage metrics
Categories
Keywords
speedMacrocycle Synthesiscyclosporin-based moleculesderisking syntheticallyprogramSAR26 macrocyclic cyclophilin inhibitorsgenotype coveragemethodHCVdesign decisionsprioritizing compound ideasRecent advancesMUEdevelopment efforthepatitis C virusFEPhost target inhibitorsdrug discovery processenergy perturbationcyclophilin inhibitorsFree Energy Calculationshepatitis Caccuracychemistry efforts
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC