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

Doaa A Osman,Mario A Macías,Luke S Zondagh,Jacques Joubert,Ali A El-Emam,Lamya H Al-Wahaibi,Nora H Al-Shaalan,Santiago Garcia-Granda

doi:10.3390/molecules26175335

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.

Highlights

Significant attention has been devoted to adamantane-based derivatives which have long been identified for their assorted biological properties [1,2,3]
Based on the docking results, we propose a series of compounds (D1–D9, Figure 12) based on the structures of compounds 1–3 as potential 11β-HSD1 inhibitors with improved binding interactions and binding affinity scores
In order to obtain a better understanding of the crystal packing, the crystallographic analysis was complemented with theoretical calculations using the Crystallographic Information File (CIF) obtained from the X-ray results

Summary

Introduction

Significant attention has been devoted to adamantane-based derivatives which have long been identified for their assorted biological properties [1,2,3]. The dipeptidyl peptidase IV (DPP-IV) adamantane-based drugs vildagliptin [12] and saxagliptin [13] are currently used as oral hypoglycemic agents for the treatment of type 2 diabetes. The adamantane-linked 1,2,4-triazole derivatives I, II and III were discovered as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) [14,15]. The non-adamantyl 1,2,4-triazoles IV [16], V [17] and VI [18] are presently under clinical investigations as 11β-HSD1 inhibitors for the treatment of type 2 diabetes and obesity (Figure 1). The development of selective 11β-HSD1 inhibitors would be an important therapy for non-insulin-dependent diabetes, hyperglycemia, obesity, insulin resistance, hyperlipidemia, hypertension and other symptoms associated with excessive body cortisol [20,21,22]

Methods

Results

Conclusion