Encoding mu-opioid receptor biased agonism with interaction fingerprints
Por:
Bruno Hernandez-Alvarado, R., Madariaga-Mazon, Abraham, Cosme-Vela, Fernando, Marmolejo-Valencia, Andres F., Nefzi, Adel, Martinez-Mayorga, Karina
Publicada:
1 nov 2021
Ahead of Print:
1 oct 2021
Resumen:
Opioids are potent painkillers, however, their therapeutic use requires
close medical monitoring to diminish the risk of severe adverse effects.
The G-protein biased agonists of the mu-opioid receptor (MOR) have shown
safer therapeutic profiles than non-biased ligands. In this work, we
performed extensive all-atom molecular dynamics simulations of two
markedly biased ligands and a balanced reference molecule. From those
simulations, we identified a protein-ligand interaction fingerprint that
characterizes biased ligands. Then, we built and virtually screened a
database containing 68,740 ligands with proven or potential GPCR
agonistic activity. Exemplary molecules that fulfill the interacting
pattern for biased agonism are showcased, illustrating the usefulness of
this work for the search of biased MOR ligands and how this contributes
to the understanding of MOR biased signaling.
Filiaciones:
Bruno Hernandez-Alvarado, R.:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City, DF, Mexico
Madariaga-Mazon, Abraham:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City, DF, Mexico
Cosme-Vela, Fernando:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City, DF, Mexico
Marmolejo-Valencia, Andres F.:
Univ Nacl Autonoma Mexico, Fac Quim, Mexico City, DF, Mexico
Nefzi, Adel:
Florida Int Univ, Ctr Translat Sci, Port St Lucie, FL USA
Torrey Pines Inst Mol Studies, Port St Lucie, FL USA
Martinez-Mayorga, Karina:
Univ Nacl Autonoma Mexico, Inst Quim, Mexico City, DF, Mexico
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