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© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
Structural Insights and Docking Analysis of Adamantane-Linked 1,2,4-Triazole Derivatives as Potential 11β-HSD1 Inhibitors
Author
Osman, Doaa A 1 ; Macías, Mario A 2 ; Al-Wahaibi, Lamya H 3 ; Al-Shaalan, Nora H 3 ; Zondagh, Luke S 4   VIAFID ORCID Logo  ; Joubert, Jacques 4   VIAFID ORCID Logo  ; Garcia-Granda, Santiago 1   VIAFID ORCID Logo  ; El-Emam, Ali A 5 

 Department of Physical and Analytical Chemistry, Faculty of Chemistry, Oviedo University-CINN, 33006 Oviedo, Spain; [email protected] (D.A.O.); [email protected] (S.G.-G.) 
 Crystallography and Chemistry of Materials, CrisQuimMat, Department of Chemistry, Universidad de Los Andes, Carrera 1 No. 18A-10, Bogotá 111711, Colombia; [email protected] 
 Department of Chemistry, College of Sciences, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia; [email protected] 
 Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville 7535, South Africa; [email protected] (L.S.Z.); [email protected] (J.J.) 
 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt 
First page
5335
Publication year
2021
Publication date
2021
Publisher
MDPI AG
e-ISSN
14203049
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2571437294
Copyright
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.