Insights from Fragment Hit Binding Assays by Molecular Simulations.
J Chem Inf Model
; 55(10): 2200-5, 2015 Oct 26.
Article
em En
| MEDLINE
| ID: mdl-26376295
ABSTRACT
Novel bioactive molecules can be rationally designed by growing and linking small fragments. Because fragments are fast and promiscuous, it is common to have contradictory hit results between different experimental screening techniques. Here, we simultaneously determine fragment binding poses, affinities, and kinetics on a focused library of 42 fragments against the serine protease factor Xa using multimillisecond molecular dynamics simulations. We predict experimental poses of 12 over 15 S1 crystal structures, and affinities are recovered for 4 out of 6. A kinetic map of protein cavities is computed in terms of on- and off-rates as well as insights into secondary ligand poses. The results suggest that the approach can be useful to recapitulate discordant fragment screening data.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Fator Xa
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Bibliotecas de Moléculas Pequenas
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Simulação de Dinâmica Molecular
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article