TY - JOUR
T1 - Molecular docking and dynamic simulations of quinoxaline 1,4-di-N-oxide as inhibitors for targets from Trypanosoma cruzi , Trichomonas vaginalis, and Fasciola hepatica
AU - González-González, Alonzo
AU - Méndez-Álvarez, Domingo
AU - Vázquez-Jiménez, Lenci K.
AU - Delgado-Maldonado, Timoteo
AU - Ortiz-Pérez, Eyra
AU - Paz-González, Alma D.
AU - Bandyopadhyay, Debasish
AU - Rivera, Gildardo
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2023/6
Y1 - 2023/6
N2 - Context: Quinoxaline 1,4-di-N-oxide is a scaffold with a wide array of biological activities, particularly its use to develop new antiparasitic agents. Recently, these compounds have been described as trypanothione reductase (TR), triosephosphate isomerase (TIM), and cathepsin-L (CatL) inhibitors from Trypanosoma cruzi, Trichomonas vaginalis, and Fasciola hepatica, respectively. Methods: Therefore, the main objective of this work was to analyze quinoxaline 1,4-di-N-oxide derivatives of two databases (ZINC15 and PubChem) and literature by molecular docking, dynamic simulation and complemented by MMPBSA, and contact analysis of molecular dynamics’ trajectory on the active site of the enzymes to know their potential effect inhibitory. Interestingly, compounds Lit_C777 and Zn_C38 show preference as potential TcTR inhibitors over HsGR, with favorable energy contributions from residues including Pro398 and Leu399 from Z-site, Glu467 from γ-Glu site, and His461, part of the catalytic triad. Compound Lit_C208 shows potential selective inhibition against TvTIM over HsTIM, with favorable energy contributions toward TvTIM catalytic dyad, but away from HsTIM catalytic dyad. Compound Lit_C388 was most stable in FhCatL with a higher calculated binding energy by MMPBSA analysis than HsCatL, though not interacting with catalytic dyad, holding favorable energy contribution from residues oriented at FhCatL catalytic dyad. Therefore, these kinds of compounds are good candidates to continue researching and confirming their activity through in vitro studies as new selective antiparasitic agents.
AB - Context: Quinoxaline 1,4-di-N-oxide is a scaffold with a wide array of biological activities, particularly its use to develop new antiparasitic agents. Recently, these compounds have been described as trypanothione reductase (TR), triosephosphate isomerase (TIM), and cathepsin-L (CatL) inhibitors from Trypanosoma cruzi, Trichomonas vaginalis, and Fasciola hepatica, respectively. Methods: Therefore, the main objective of this work was to analyze quinoxaline 1,4-di-N-oxide derivatives of two databases (ZINC15 and PubChem) and literature by molecular docking, dynamic simulation and complemented by MMPBSA, and contact analysis of molecular dynamics’ trajectory on the active site of the enzymes to know their potential effect inhibitory. Interestingly, compounds Lit_C777 and Zn_C38 show preference as potential TcTR inhibitors over HsGR, with favorable energy contributions from residues including Pro398 and Leu399 from Z-site, Glu467 from γ-Glu site, and His461, part of the catalytic triad. Compound Lit_C208 shows potential selective inhibition against TvTIM over HsTIM, with favorable energy contributions toward TvTIM catalytic dyad, but away from HsTIM catalytic dyad. Compound Lit_C388 was most stable in FhCatL with a higher calculated binding energy by MMPBSA analysis than HsCatL, though not interacting with catalytic dyad, holding favorable energy contribution from residues oriented at FhCatL catalytic dyad. Therefore, these kinds of compounds are good candidates to continue researching and confirming their activity through in vitro studies as new selective antiparasitic agents.
KW - Cathepsin-L
KW - Fasciola hepatica
KW - Quinoxaline 1,4-di-N-oxide
KW - Trichomonas vaginalis
KW - Triosephosphate isomerase
KW - Trypanosoma cruzi
KW - Trypanothione reductase
UR - http://www.scopus.com/inward/record.url?scp=85159650878&partnerID=8YFLogxK
U2 - 10.1007/s00894-023-05579-4
DO - 10.1007/s00894-023-05579-4
M3 - Artículo
C2 - 37195391
AN - SCOPUS:85159650878
SN - 1610-2940
VL - 29
JO - Journal of Molecular Modeling
JF - Journal of Molecular Modeling
IS - 6
M1 - 180
ER -