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

Abstract

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.

Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11β-HSD1 Molecular Docking and ADMET Prediction

“…In silico drug design methods, such as molecular docking, are recognized to play an essential role in the development of novel therapeutics. In previous studies [ 24 , 25 , 28 ], compounds containing structural motifs, such as adamantane and triazole moieties, exhibited potent 11β-HSD1 inhibitory activities. Compounds 2 and 3 have previously been evaluated for their in vivo hypoglycemic activity.…”

“…Therefore, we conducted molecular docking of the crystallized compounds 1 , 2 and 3 , in order to determine their potential as 11β-HSD1 inhibitors. The X-ray 11β-HSD1 protein (PDB ID: 4C7J ) was utilized for its reliability to reproduce binding poses of known 11β-HSD1 inhibitors [ 25 ], as well as the co-crystallized inhibitor 4-cyclopropyl- N -(trans-5-hydroxy-2-adamantyl)-2-(2-hydroxyethoxy)-thiazole-5-carboxamide ( 4YQ , 11β-HSD1 IC 50 = 9.9 nM) [ 28 ], which contains similar structural features as compounds 1 – 3 . The compounds were docked within 11β-HSD1, and exhibited promising binding affinity scores and binding interactions with important active site residues.…”

“…In addition, the desadamantyl 1,2,4-triazole derivatives IV [21], V [22] and VI [23], are currently under clinical investigations as 11β-HSD1 inhibitors for the treatment of type 2 diabetes and obesity (Figure 1). According to experimental and molecular docking studies for the identification of chemical features of 11β-HSD1 inhibitors, a combination of an adamantane cage-and 1,2,4-triazole or other azole moieties could result in potent 11β-HSD1 inhibitors [15,16,[24][25][26][27][28][29]. In continuation with ongoing interest in the structural properties [30][31][32][33][34][35] and biological applications of adamantane-based derivatives [35][36][37][38][39], we report herein on the molecular structure insights, Hirshfeld surface analysis and pairwise interaction energies of three adamantane-linked 1,2,4-triazole N-Mannich bases, namely ethyl 4-[(3adamantan-1-yl)-4-ethyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)methyl]piperazine-1carboxylate (1), 5-(adamantan-1-yl)-4-ethyl-2-[(4-(pyridin-2-yl)piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (2) and 5-(adamantan-1-yl)-4-allyl-2-[(4-(pyridin-2yl)piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (3), which were proven to possess marked hypoglycemic activity [39].…”

“…In addition, the des-adamantyl 1,2,4-triazole derivatives IV [ 21 ], V [ 22 ] and VI [ 23 ], are currently under clinical investigations as 11β-HSD1 inhibitors for the treatment of type 2 diabetes and obesity ( Figure 1 ). According to experimental and molecular docking studies for the identification of chemical features of 11β-HSD1 inhibitors, a combination of an adamantane cage- and 1,2,4-triazole or other azole moieties could result in potent 11β-HSD1 inhibitors [ 15 , 16 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

Hirshfeld Surface Analysis for Investigation of Intermolecular Interaction of Molecular Crystals

“…Hydrophobic effects may also need to be considered in the case between hydrogen atoms. Daśko et al for interactions of ketoprofen crystals that support theoretical docking simulations [35].…”