Design and evaluation of novel triazole derivatives as potential anti-gout inhibitors: A comprehensive molecular modeling study

Mohammed Er-rajy ^1* Mohamed El fadili ¹ Sara Zarougui ¹ Somdutt Mujwar ² Mourad Aloui ¹ Mohammed Zerrouk ¹ Belkheir Hammouti ³ Larbi Rhazi ⁴ Rachid Sabbahi ⁵ Mohammed M. Alanazi ⁶ AZZAOUI KHALIL ⁷ Rachid SALGHI ⁸ Menana Elhallaoui ¹

• ¹ Sidi Mohamed Ben Abdellah University, Fes, Morocco
• ² Chitkara University, Chandigarh, Punjab, India
• ³ Euromed University, Fez, Fes-Meknes, Morocco
• ⁴ Université d'Artois, Arras, Hauts-de-France, France
• ⁵ Research Team in Science and Technology, Higher School of Technology, Ibn Zohr University, P.O. Box 3007, Laayoune, Morocco., laayone, Morocco
• ⁶ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
• ⁷ 3Engineering Laboratory of Organometallic, Molecular Materials and Environment, Faculty of Sciences, Sidi Mohammed Ben Abdellah University, 30000 Fez, Morocco, fez, Morocco
• ⁸ 8Laboratory of Applied Chemistry and Environment, ENSA, University Ibn Zohr, PO Box 1136, Agadir 80000, Morocco, agadir, Morocco

Drug design is undergoing a major revolution as diseases continue to progress, with each disease leading to another. Our work focuses on a series of synthesized anti-xanthine oxidase inhibitors, aiming to develop new inhibitors. A computational study was carried out to identify the xanthine oxidase inhibitory structural features of a series of triazole inhibitors using computational method. The optimal model established from CoMFA and CoMSIA/SEA was successfully evaluated for its predictive capability. Visualization of the contour maps of both models showed that modifying the substituents plays a key role in enhancing the biological activity of anti-gout inhibitors. Molecular docking results for complexes N°8-3NVY and N°22-3NVY showed scores of -7.22 kcal/mol and -8.36 kcal/mol, respectively, indicating substantial affinity for the enzyme. Complex N°8-3NVY forms two hydrogen bonds with SER 69 and ASN 71, three alkyl bonds with ALA 70, LEU 74, and ALA 75, and one Pi-Pi T-shaped bond with PHE 68. Complex N°22-3NVY forms three hydrogen bonds with HIS 99, ARG 29, and ILE 91, and one halogen bond with LEU 128 at 3.60 Å. A MD study revealed that the N°22-3NVY complex remained highly stable throughout the simulation. Therefore, we proposed six new molecules, their anti-gout inhibitory activities were predicted using two models, and they were evaluated for Lipinski's rule, and ADMET properties. The results show that both Pred 4 and Pred 5 have better pharmacokinetic properties than the height potent molecule in the studied series, making these two compounds valuable candidates for new anti-gout drugs.Subsequently, using DFT study to evaluate the chemical reactivity properties of these two proposed compounds, the energy gap results revealed that both molecules exhibit moderate chemical stability and reactivity.