Structural Insights and Docking Analysis of Adamantane-Linked 1,2,4-Triazole Derivatives as Potential 11β-HSD1 Inhibitors

Molecules

Mario A. Macías¹  Nora H. Al-Shaalan²  Lamya H. Al-Wahaibi²  Ali A. El-Emam³  Doaa A. Osman⁴  Santiago Garcia-Granda⁴  Luke S. Zondagh⁵  Jacques Joubert⁵ 

[1] Crystallography and Chemistry of Materials, CrisQuimMat, Department of Chemistry, Universidad de Los Andes, Carrera 1 No. 18A-10, Bogotá 111711, Colombia;Department of Chemistry, College of Sciences, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia;Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;Department of Physical and Analytical Chemistry, Faculty of Chemistry, Oviedo University-CINN, 33006 Oviedo, Spain;Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa;

关键词: adamantane;    1,2,4-triazole;    single crystal X-ray;    Hirshfeld surface analysis;    molecular docking;    ADME;   

DOI  :  10.3390/molecules26175335

来源: DOAJ

【 摘 要 】

The solid-state structural analysis and docking studies of three adamantane-linked 1,2,4-triazole derivatives are presented. Crystal structure analyses revealed that compound 2 crystallizes in the triclinic P-1 space group, while compounds 1 and 3 crystallize in the same monoclinic P2₁/c space group. Since the only difference between them is the para substitution on the aryl group, the electronic nature of these NO₂ and halogen groups seems to have no influence over the formation of the solid. However, a probable correlation with the size of the groups is not discarded due to the similar intermolecular disposition between the NO₂/Cl substituted molecules. Despite the similarities, CE-B3LYP energy model calculations show that pairwise interaction energies vary between them, and therefore the total packing energy is affected. HOMO-LUMO calculated energies show that the NO₂ group influences the reactivity properties characterizing the molecule as soft and with the best disposition to accept electrons. Further, in silico studies predicted that the compounds might be able to inhibit the 11β-HSD1 enzyme, which is implicated in obesity and diabetes. Self- and cross-docking experiments revealed that a number of non-native 11β-HSD1 inhibitors were able to accurately dock within the 11β-HSD1 X-ray structure 4C7J. The molecular docking of the adamantane-linked 1,2,4-triazoles have similar predicted binding affinity scores compared to the 4C7J native ligand 4YQ. However, they were unable to form interactions with key active site residues. Based on these docking results, a series of potentially improved compounds were designed using computer aided drug design tools. The docking results of the new compounds showed similar predicted 11β-HSD1 binding affinity scores as well as interactions to a known potent 11β-HSD1 inhibitor.

【 授权许可】

Unknown