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. 2012 Jun 25;7(18):1398-405.
doi: 10.3969/j.issn.1673-5374.2012.18.006.

Three-dimensional pharmacophore screening for fentanyl derivatives

Ming Liu  1 , Zhiguo Sun  2 , Wenxiang Hu  3
Affiliations

Three-dimensional pharmacophore screening for fentanyl derivatives

Ming Liu et al. Neural Regen Res. .

Abstract

Fentanyl is a highly selective μ-opioid receptor agonist with high analgesic activity. Three-dimensional pharmacophore models were built from a set of 50 fentanyl derivatives. These were employed to elucidate ligand-receptor interactions using information derived only from the ligand structure to identify new potential lead compounds. The present studies demonstrated that three hydrophobic regions, one positive ionizable region and two hydrogen bond acceptor region sites located on the molecule seem to be essential for analgesic activity. The results of the comparative molecular field analysis model suggested that both steric and electrostatic interactions play important roles. The contributions from steric and electrostatic fields for the model were 0.621 and 0.379, respectively. The pharmacophore model provides crucial information about how well the common features of a subject molecule overlap with the hypothesis model, which is very valuable for designing and optimizing new active structures.

Keywords: analgesic; comparative molecular field analysis; fentanyl; genetic algorithm with linear assignment of hypermolecular alignment of datasets; pharmacophore.

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Conflict of interest statement

Conflicts of interest: None declared.

Figures

Figure 1
Figure 1
The structures of commercially available fentanyl-like compounds. (A) Fentanyl; (B) Suentanli; (C) Remifentanil; (D) Alfentanil.
Figure 2
Figure 2
Compound 1 (left) and compound 2 (right) structures used for pharmacophore screening.
Figure 3
Figure 3
Stereoview of the aligned congruent molecules. Different colors represent different substituents and groups.
Figure 4
Figure 4
Congruent molecules for quantitative structure-activity relationship calculation. Different colors represent different substituents and groups.
Figure 5
Figure 5
The best hypothesis of compound G_2 mapping to model 19.
Figure 6
Figure 6
Essential features of model 19 pharmacophore.
Figure 7
Figure 7
Comparative molecular field analysis (CoMFA) steric and electrostatic contour with μ opioid receptor plot from partial least squares analysis. The green polyhedron located at the N substitute of pyridine ring indicates bulky substituents. At the benzene ring position, there is a relatively large yellow region suggesting substituent on this position. The red polyhedron located at R2 substituent position suggests negative atom or group
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