TY  - JOUR
AU  - Kováčiková, Lucia
AU  - Gaikwad, Sunil
AU  - Almášiová, Kristína
AU  - Almássy, Ambroz
AU  - Addová, Gabriela
AU  - Májeková, Magdaléna
AU  - Hanquet, Gilles
AU  - Dobričić, Vladimir
AU  - Boháč, Andrej
AU  - Štefek, Milan
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5545
AB  - Novel oxotriazinoindoles (OTIs) were recently reported as highly efficient and selective aldose reductase inhibitors. Here, a series of novel N(2)-substituted oxotriazinoindoles was developed with the aim to investigate molecular interactions within the aldose reductase (ALR2) inhibitor binding site. About twice increased inhibition efficacy of the most efficient derivative 14 (N(2)-CH2CH2COOH) compared to the unsubstituted lead OTI was obtained, yet at the expense of selectivity relative to anti-target aldehyde reductase (ALR1). To explain the major drop in selectivity, observed also in other N(2)-substituted derivatives, in silico molecular modeling approach revealed the role of extra interactions with the residues of Arg309, Arg312 and Met302 located in the additional C-terminal loop of ALR1 missing in ALR2, which can prevent or enhance binding in ALR1. These key findings will be used for development of the next generation of selective OTI inhibitors. (Figure presented.).
PB  - Springer
T2  - Medicinal Chemistry Research
T1  - Selectivity of N(2)-substituted oxotriazinoindole aldose reductase inhibitors is determined by the interaction pattern with Pro301-Arg312 loop of aldehyde reductase
VL  - 33
SP  - 492
EP  - 503
DO  - 10.1007/s00044-024-03194-3
ER  - 

@article{
author = "Kováčiková, Lucia and Gaikwad, Sunil and Almášiová, Kristína and Almássy, Ambroz and Addová, Gabriela and Májeková, Magdaléna and Hanquet, Gilles and Dobričić, Vladimir and Boháč, Andrej and Štefek, Milan",
year = "2024",
abstract = "Novel oxotriazinoindoles (OTIs) were recently reported as highly efficient and selective aldose reductase inhibitors. Here, a series of novel N(2)-substituted oxotriazinoindoles was developed with the aim to investigate molecular interactions within the aldose reductase (ALR2) inhibitor binding site. About twice increased inhibition efficacy of the most efficient derivative 14 (N(2)-CH2CH2COOH) compared to the unsubstituted lead OTI was obtained, yet at the expense of selectivity relative to anti-target aldehyde reductase (ALR1). To explain the major drop in selectivity, observed also in other N(2)-substituted derivatives, in silico molecular modeling approach revealed the role of extra interactions with the residues of Arg309, Arg312 and Met302 located in the additional C-terminal loop of ALR1 missing in ALR2, which can prevent or enhance binding in ALR1. These key findings will be used for development of the next generation of selective OTI inhibitors. (Figure presented.).",
publisher = "Springer",
journal = "Medicinal Chemistry Research",
title = "Selectivity of N(2)-substituted oxotriazinoindole aldose reductase inhibitors is determined by the interaction pattern with Pro301-Arg312 loop of aldehyde reductase",
volume = "33",
pages = "492-503",
doi = "10.1007/s00044-024-03194-3"
}

Kováčiková, L., Gaikwad, S., Almášiová, K., Almássy, A., Addová, G., Májeková, M., Hanquet, G., Dobričić, V., Boháč, A.,& Štefek, M.. (2024). Selectivity of N(2)-substituted oxotriazinoindole aldose reductase inhibitors is determined by the interaction pattern with Pro301-Arg312 loop of aldehyde reductase. in Medicinal Chemistry Research
Springer., 33, 492-503.
https://doi.org/10.1007/s00044-024-03194-3

Kováčiková L, Gaikwad S, Almášiová K, Almássy A, Addová G, Májeková M, Hanquet G, Dobričić V, Boháč A, Štefek M. Selectivity of N(2)-substituted oxotriazinoindole aldose reductase inhibitors is determined by the interaction pattern with Pro301-Arg312 loop of aldehyde reductase. in Medicinal Chemistry Research. 2024;33:492-503.
doi:10.1007/s00044-024-03194-3 .

Kováčiková, Lucia, Gaikwad, Sunil, Almášiová, Kristína, Almássy, Ambroz, Addová, Gabriela, Májeková, Magdaléna, Hanquet, Gilles, Dobričić, Vladimir, Boháč, Andrej, Štefek, Milan, "Selectivity of N(2)-substituted oxotriazinoindole aldose reductase inhibitors is determined by the interaction pattern with Pro301-Arg312 loop of aldehyde reductase" in Medicinal Chemistry Research, 33 (2024):492-503,
https://doi.org/10.1007/s00044-024-03194-3 . .