Computational Investigation of Leflunomide as a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches

Özlem Gündoğdu; Sertan Aytaç; Ebrar Nur Özkan

doi:10.18016/ksutarimdoga.vi.1812474

TR EN

Leflunomid’in Potansiyel Ksantin Oksidaz İnhibitörü Olarak Yoğunluk Fonksiyonel Teorisi (DFT) ve Moleküler Kenetlenme Yöntemleri ile Hesaplamalı Analizi

Abstract

Gut, yüksek serum ürik asit (SUA) düzeyleri ve inflamasyonla karakterize metabolik bir hastalıktır. Ürik asit üretiminde ksantin oksidaz (XO) enzimi merkezi rol oynadığından, XO inhibitörleri tedavide yaygın olarak kullanılmaktadır. Bu çalışmada Leflunomide (LEF) molekülünün yapısal, elektronik ve spektroskopik özellikleri, Yoğunluk Fonksiyonel Teorisi (DFT) ile B3LYP/6-311G(d,p) düzeyinde incelenmiştir. Geometri optimizasyonu, aromatik C–C bağlarının 1.39–1.40 Å aralığında olduğunu ve π-elektron delokalizasyonunun korunduğunu göstermiştir. Moleküldeki en uzun C–C bağları (1.54 Å) elektronegatif sübstitüentlerin etkisiyle ilişkilendirilmiştir. Bağ ve dihedral açı analizleri, özellikle amid bölgesinde konformasyonel esneklik gösteren dengeli bir üç boyutlu yapı ortaya koymuştur. HOMO–LUMO enerji aralığı 0,1953 eV olarak hesaplanmış ve LEF’in yüksek kimyasal reaktivite potansiyeline sahip olduğu belirlenmiştir. UV–Vis ve TD-DFT sonuçları, HOMO→LUMO geçiş karakterinin farklı çözücülerde korunduğunu ve küçük spektral kaymalar gözlendiğini doğrulamıştır. Mulliken yük dağılımı ve moleküler elektrostatik potansiyel (MEP) analizleri, amid N–H ve CF₃ gruplarının XO aktif bölgesinde hidrojen bağı ve elektrostatik etkileşimler için potansiyel bölgeler olduğunu göstermiştir. Solvatasyon serbest enerjisi ve dipol moment analizleri, polar ortamlarda artan kararlılık ve termodinamik olarak avantajlı yapılar göstermektedir.Moleküler kenetlenme çalışmaları, LEF’in XO ile −6,92 kcal/mol bağlanma enerjisiyle güçlü etkileşim sağladığını ve Allopurinol ile Quercetin’e kıyasla potansiyel bir XO inhibitörü olabileceğini ortaya koymuştur.

Keywords

Computational Investigation of Leflunomide as a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches

Abstract

Gout is a metabolic disorder characterized by elevated serum uric acid (SUA) levels and inflammation. Xanthine oxidase (XO) plays a central role in uric acid production, and XO inhibitors are widely used in its treatment. In this study, the structural, electronic, and spectroscopic properties of Leflunomidee (LEF) were investigated using Density Functional Theory (DFT) at the B3LYP/6-311G(d,p) level. Geometry optimization showed that aromatic C–C bond lengths range from 1.39 to 1.40 Å, indicating preserved π-electron delocalization, while the longest C–C bonds (1.54 Å) are influenced by electronegative substituents. Bond angle and dihedral analyses revealed a balanced three-dimensional structure with conformational flexibility, especially in the amide region. The HOMO–LUMO energy gap was calculated as 0.1953 eV, suggesting high chemical reactivity of LEF. UV–Vis and TD-DFT results confirmed that the HOMO→LUMO transition character is maintained across different solvents, with only minor spectral shifts. Mulliken charge and molecular electrostatic potential (MEP) analyses identified the amide N–H and CF₃ groups as potential sites for hydrogen bonding and electrostatic interactions with the XO active site. Solvation free energy and dipole moment analyses indicated enhanced stability in polar environments and thermodynamically favorable structures. Molecular docking studies showed strong binding of LEF to XO, with a binding energy of −6.92 kcal/mol, suggesting its potential as an XO inhibitor compared to Allopurinol and Quercetin.

Keywords

References

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Details

Primary Language

English

Subjects

Microbiology (Other), Pharmacology and Pharmaceutical Sciences (Other)

Journal Section

Research Article

Authors

Özlem Gündoğdu ^*
0000-0002-6943-9674
Türkiye

Sertan Aytaç
0000-0002-3196-4545
Türkiye

Ebrar Nur Özkan
0000-0002-1222-1500
Türkiye

Early Pub Date

October 23, 2026

Publication Date

-

Submission Date

October 28, 2025

Acceptance Date

May 11, 2026

Published in Issue

Year 2026 Number: Advanced Online Publication

DOI

https://doi.org/10.18016/ksutarimdoga.vi.1812474

IZ

https://izlik.org/JA93RN76UR

Cite

RIS / Bibtex

APA

Gündoğdu, Ö., Aytaç, S., & Özkan, E. N. (2026). Computational Investigation of Leflunomide as a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches. Kahramanmaraş Sütçü İmam Üniversitesi Tarım Ve Doğa Dergisi, Advanced Online Publication. https://doi.org/10.18016/ksutarimdoga.vi.1812474

AMA

1.Gündoğdu Ö, Aytaç S, Özkan EN. Computational Investigation of Leflunomide as a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches. KSU J. Agric Nat. 2026;(Advanced Online Publication). doi:10.18016/ksutarimdoga.vi.1812474

Chicago

Gündoğdu, Özlem, Sertan Aytaç, and Ebrar Nur Özkan. 2026. “Computational Investigation of Leflunomide As a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches”. Kahramanmaraş Sütçü İmam Üniversitesi Tarım Ve Doğa Dergisi, no. Advanced Online Publication. https://doi.org/10.18016/ksutarimdoga.vi.1812474.

EndNote

Gündoğdu Ö, Aytaç S, Özkan EN (October 1, 2026) Computational Investigation of Leflunomide as a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches. Kahramanmaraş Sütçü İmam Üniversitesi Tarım ve Doğa Dergisi Advanced Online Publication

IEEE

[1]Ö. Gündoğdu, S. Aytaç, and E. N. Özkan, “Computational Investigation of Leflunomide as a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches”, KSU J. Agric Nat., no. Advanced Online Publication, Oct. 2026, doi: 10.18016/ksutarimdoga.vi.1812474.

ISNAD

Gündoğdu, Özlem - Aytaç, Sertan - Özkan, Ebrar Nur. “Computational Investigation of Leflunomide As a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches”. Kahramanmaraş Sütçü İmam Üniversitesi Tarım ve Doğa Dergisi. Advanced Online Publication (October 1, 2026). https://doi.org/10.18016/ksutarimdoga.vi.1812474.

JAMA

1.Gündoğdu Ö, Aytaç S, Özkan EN. Computational Investigation of Leflunomide as a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches. KSU J. Agric Nat. 2026. doi:10.18016/ksutarimdoga.vi.1812474.

MLA

Gündoğdu, Özlem, et al. “Computational Investigation of Leflunomide As a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches”. Kahramanmaraş Sütçü İmam Üniversitesi Tarım Ve Doğa Dergisi, no. Advanced Online Publication, Oct. 2026, doi:10.18016/ksutarimdoga.vi.1812474.

Vancouver

1.Özlem Gündoğdu, Sertan Aytaç, Ebrar Nur Özkan. Computational Investigation of Leflunomide as a Potential Xanthine Oxidase Inhibitor Using DFT and Molecular Docking Approaches. KSU J. Agric Nat. 2026 Oct. 1;(Advanced Online Publication). doi:10.18016/ksutarimdoga.vi.1812474