Limits...
Three-dimensional pharmacophore screening for fentanyl derivatives.

Liu M, Sun Z, Hu W - Neural Regen Res (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: College of Life Science, Capital Normal University, Beijing 100048, China.

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.

No MeSH data available.


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
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4308790&req=5

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

Mentions: The analysis of CoMFA contour maps provided insights into possible modification of the molecules for higher activity. Favored and disfavored levels, fixed at 80% and 20%, respectively, were used to display steric and electrostatic fields (Figure 7). The contours for steric fields are shown in green (more bulk favored) and yellow (less bulk favored), whereas the electrostatic field contours are shown in red (electronegative substituents favored) and blue (electropositive substituents favored). The green polyhedron located at the N substituent of the pyridine ring indicated that bulky substituents would be favorable. This explains why compounds 1, 2, 3 and 4 had relatively lower activity than other compounds with a bulky replacement at the N position. At the benzene-ring position, there was a relatively large yellow region. This suggested that substituents on this position could not be too bulky otherwise lower activity would result, so no substituents or small groups on the benzene ring were permitted[1528]. The red polyhedron located at the R2 substituent position suggested that a negatively charged atom or group may increase activity, so electron-rich atoms and groups at this position showed strong activity. This was why compounds 10, 13, 16 and 19 were more potent than compounds 8, 11, 14 and 17, respectively. The large blue polyhedral circling the pyridine ring suggested that substitution by electropositive elements on the pyridine ring were favorable (i.e., that positively charged groups such as NO2, CN and F would show more potent activity). The respective relative contributions of steric and electrostatic fields were 0.481 and 0.519, respectively, indicating that the electrostatic field was predominant.


Three-dimensional pharmacophore screening for fentanyl derivatives.

Liu M, Sun Z, Hu W - Neural Regen Res (2012)

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
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4308790&req=5

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
Mentions: The analysis of CoMFA contour maps provided insights into possible modification of the molecules for higher activity. Favored and disfavored levels, fixed at 80% and 20%, respectively, were used to display steric and electrostatic fields (Figure 7). The contours for steric fields are shown in green (more bulk favored) and yellow (less bulk favored), whereas the electrostatic field contours are shown in red (electronegative substituents favored) and blue (electropositive substituents favored). The green polyhedron located at the N substituent of the pyridine ring indicated that bulky substituents would be favorable. This explains why compounds 1, 2, 3 and 4 had relatively lower activity than other compounds with a bulky replacement at the N position. At the benzene-ring position, there was a relatively large yellow region. This suggested that substituents on this position could not be too bulky otherwise lower activity would result, so no substituents or small groups on the benzene ring were permitted[1528]. The red polyhedron located at the R2 substituent position suggested that a negatively charged atom or group may increase activity, so electron-rich atoms and groups at this position showed strong activity. This was why compounds 10, 13, 16 and 19 were more potent than compounds 8, 11, 14 and 17, respectively. The large blue polyhedral circling the pyridine ring suggested that substitution by electropositive elements on the pyridine ring were favorable (i.e., that positively charged groups such as NO2, CN and F would show more potent activity). The respective relative contributions of steric and electrostatic fields were 0.481 and 0.519, respectively, indicating that the electrostatic field was predominant.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: College of Life Science, Capital Normal University, Beijing 100048, China.

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.

No MeSH data available.