Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives
Inhibicija ksantin oksidaze derivatima 1,2,3,4-tetrahidroizohinolina
Autori
Gajić, MihajloIlić, Budimir S.
Bondžić, Bojan
Džambaski, Zdravko
Filipović, Ana
Kocić, Gordana
Šmelcerović, Andrija
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
Xanthine oxidase (XO) is a versatile metalloflavoprotein enzyme that is best known for its rate-limiting role in the purine degradation pathway. Therapeutic inhibition of XO is based on its role in a variety of diseases that is attributed either to the hyperproduction of uric acid, or the hyperproduction of reactive oxygen species. Herein, we report the assessment of XO inhibitory properties of 24 1,2,3,4-tetrahydroisoquinoline derivatives, among which compound
16 exhibited IC50 value of 135.72 ± 2.71 µM. The interaction of compound 16 with XO enzyme was simulated using the Site Finder module, molecular docking and molecular dynamics. Molecular modeling suggests that interactions with Met 1038, Gln 1040, Thr 1077, Gln 1194 and Val 1259 are an important factor for inhibitor affinity toward the XO enzyme. Our proposed binding model might be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of XO enzyme.
Ksantin oksidaza (XO) je metaloflavoproteinski enzim, koji je najpoznatiji po svojoj ulozi ograničavanja brzine razgradnje purinskih nukleotida. Terapijska inhibicija XO zasniva se na njenoj ulozi u brojnim bolestima, koje su povezane bilo sa hiperprodukcijom mokraćne kiseline ili hiperprodukcijom reaktivnih kiseoničnih vrsta. U ovom radu izvršeno je ispitivanje sposobnosti inhibicije XO 24 derivata 1,2,3,4-tetrahidroizohinolina, od kojih je jedinjenje 16 pokazalo IC50 vrednost od 135,72 µM ± 2,71 µM. Interakcija jedinjenja 16 sa XO enzimom simulirana je korišćenjem Site Finder modula molekularnog dokinga i molekularne dinamike. Molekulsko modelovanje ukazuje na to da su interakcije sa Met 1038, Gln 1040, Thr 1077, Gln 1194 i Val 1259 važan faktor postojanja afiniteta inhibitora prema XO enzimu. Naš predloženi model vezivanja mogao bi biti od značaja za razvoj novih aktivnih inhibitora XO zasnovanih na 1,2,3,4-tetrahidroizohinolinskom heterociklusu.
Ključne reči:
xanthine oxidase inhibition / 1,2,3,4-tetrahydroisoquinolines / molecular docking / molecular dynamic simulationIzvor:
Acta Medica Medianae, 2021, 60, 1, 48-55Izdavač:
- Acta Medica Medianae
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200113 (Univerzitet u Nišu, Medicinski fakultet) (RS-MESTD-inst-2020-200113)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200026 (Univerzitet u Beogradu, Institut za hemiju, tehnologiju i metalurgiju - IHTM) (RS-MESTD-inst-2020-200026)
- Faculty of Medicine of the University of Niš (Internal project No. 40)
Institucija/grupa
IHTMTY - JOUR AU - Gajić, Mihajlo AU - Ilić, Budimir S. AU - Bondžić, Bojan AU - Džambaski, Zdravko AU - Filipović, Ana AU - Kocić, Gordana AU - Šmelcerović, Andrija PY - 2021 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/6939 AB - Xanthine oxidase (XO) is a versatile metalloflavoprotein enzyme that is best known for its rate-limiting role in the purine degradation pathway. Therapeutic inhibition of XO is based on its role in a variety of diseases that is attributed either to the hyperproduction of uric acid, or the hyperproduction of reactive oxygen species. Herein, we report the assessment of XO inhibitory properties of 24 1,2,3,4-tetrahydroisoquinoline derivatives, among which compound 16 exhibited IC50 value of 135.72 ± 2.71 µM. The interaction of compound 16 with XO enzyme was simulated using the Site Finder module, molecular docking and molecular dynamics. Molecular modeling suggests that interactions with Met 1038, Gln 1040, Thr 1077, Gln 1194 and Val 1259 are an important factor for inhibitor affinity toward the XO enzyme. Our proposed binding model might be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of XO enzyme. AB - Ksantin oksidaza (XO) je metaloflavoproteinski enzim, koji je najpoznatiji po svojoj ulozi ograničavanja brzine razgradnje purinskih nukleotida. Terapijska inhibicija XO zasniva se na njenoj ulozi u brojnim bolestima, koje su povezane bilo sa hiperprodukcijom mokraćne kiseline ili hiperprodukcijom reaktivnih kiseoničnih vrsta. U ovom radu izvršeno je ispitivanje sposobnosti inhibicije XO 24 derivata 1,2,3,4-tetrahidroizohinolina, od kojih je jedinjenje 16 pokazalo IC50 vrednost od 135,72 µM ± 2,71 µM. Interakcija jedinjenja 16 sa XO enzimom simulirana je korišćenjem Site Finder modula molekularnog dokinga i molekularne dinamike. Molekulsko modelovanje ukazuje na to da su interakcije sa Met 1038, Gln 1040, Thr 1077, Gln 1194 i Val 1259 važan faktor postojanja afiniteta inhibitora prema XO enzimu. Naš predloženi model vezivanja mogao bi biti od značaja za razvoj novih aktivnih inhibitora XO zasnovanih na 1,2,3,4-tetrahidroizohinolinskom heterociklusu. PB - Acta Medica Medianae T2 - Acta Medica Medianae T1 - Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives T1 - Inhibicija ksantin oksidaze derivatima 1,2,3,4-tetrahidroizohinolina VL - 60 IS - 1 SP - 48 EP - 55 DO - 10.5633/amm.2021.0106 ER -
@article{ author = "Gajić, Mihajlo and Ilić, Budimir S. and Bondžić, Bojan and Džambaski, Zdravko and Filipović, Ana and Kocić, Gordana and Šmelcerović, Andrija", year = "2021", abstract = "Xanthine oxidase (XO) is a versatile metalloflavoprotein enzyme that is best known for its rate-limiting role in the purine degradation pathway. Therapeutic inhibition of XO is based on its role in a variety of diseases that is attributed either to the hyperproduction of uric acid, or the hyperproduction of reactive oxygen species. Herein, we report the assessment of XO inhibitory properties of 24 1,2,3,4-tetrahydroisoquinoline derivatives, among which compound 16 exhibited IC50 value of 135.72 ± 2.71 µM. The interaction of compound 16 with XO enzyme was simulated using the Site Finder module, molecular docking and molecular dynamics. Molecular modeling suggests that interactions with Met 1038, Gln 1040, Thr 1077, Gln 1194 and Val 1259 are an important factor for inhibitor affinity toward the XO enzyme. Our proposed binding model might be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of XO enzyme., Ksantin oksidaza (XO) je metaloflavoproteinski enzim, koji je najpoznatiji po svojoj ulozi ograničavanja brzine razgradnje purinskih nukleotida. Terapijska inhibicija XO zasniva se na njenoj ulozi u brojnim bolestima, koje su povezane bilo sa hiperprodukcijom mokraćne kiseline ili hiperprodukcijom reaktivnih kiseoničnih vrsta. U ovom radu izvršeno je ispitivanje sposobnosti inhibicije XO 24 derivata 1,2,3,4-tetrahidroizohinolina, od kojih je jedinjenje 16 pokazalo IC50 vrednost od 135,72 µM ± 2,71 µM. Interakcija jedinjenja 16 sa XO enzimom simulirana je korišćenjem Site Finder modula molekularnog dokinga i molekularne dinamike. Molekulsko modelovanje ukazuje na to da su interakcije sa Met 1038, Gln 1040, Thr 1077, Gln 1194 i Val 1259 važan faktor postojanja afiniteta inhibitora prema XO enzimu. Naš predloženi model vezivanja mogao bi biti od značaja za razvoj novih aktivnih inhibitora XO zasnovanih na 1,2,3,4-tetrahidroizohinolinskom heterociklusu.", publisher = "Acta Medica Medianae", journal = "Acta Medica Medianae", title = "Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives, Inhibicija ksantin oksidaze derivatima 1,2,3,4-tetrahidroizohinolina", volume = "60", number = "1", pages = "48-55", doi = "10.5633/amm.2021.0106" }
Gajić, M., Ilić, B. S., Bondžić, B., Džambaski, Z., Filipović, A., Kocić, G.,& Šmelcerović, A.. (2021). Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives. in Acta Medica Medianae Acta Medica Medianae., 60(1), 48-55. https://doi.org/10.5633/amm.2021.0106
Gajić M, Ilić BS, Bondžić B, Džambaski Z, Filipović A, Kocić G, Šmelcerović A. Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives. in Acta Medica Medianae. 2021;60(1):48-55. doi:10.5633/amm.2021.0106 .
Gajić, Mihajlo, Ilić, Budimir S., Bondžić, Bojan, Džambaski, Zdravko, Filipović, Ana, Kocić, Gordana, Šmelcerović, Andrija, "Xanthine Oxidase Inhibitory Properties of 1,2,3,4–Tetrahydroisoquinoline Derivatives" in Acta Medica Medianae, 60, no. 1 (2021):48-55, https://doi.org/10.5633/amm.2021.0106 . .