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Phosphodiesterase-1 Inhibitory Activity of Two Flavonoids Isolated from Pistacia integerrima J. L. Stewart Galls.

Rauf A, Saleem M, Uddin G, Siddiqui BS, Khan H, Raza M, Hamid SZ, Khan A, Maione F, Mascolo N, De Feo V - Evid Based Complement Alternat Med (2015)

Bottom Line: However, until now, the molecular mechanisms of action of "karkatshringi" and its chemical characterization are partially known.This study deals with the isolation and characterization of the active constituents from the methanolic extract of P. integerrima galls and it was also oriented to evaluate in vitro and in silico their potential enzymatic inhibitory activity against phosphodiesterase-1 (PDE1), a well-known enzyme involved in airway smooth muscle activity and airway inflammation.Our results showed that the methanolic extract of P. integerrima galls and some of its active constituents [naringenin (1) and 3,5,7,4'-tetrahydroxy-flavanone (2)] are able in vitro to inhibit PDE1 activity (59.20 ± 4.95%, 75.90 ± 5.90%, and 65.25 ± 5.25%, resp.) and demonstrate in silico an interesting interaction with this enzymatic site.

View Article: PubMed Central - PubMed

Affiliation: Institute of Chemical Sciences, University of Peshawar, Peshawar, Khyber Pakhtunkhwa 25120, Pakistan.

ABSTRACT
Pistacia integerrima is one of twenty species among the genus Pistacia. Long horn-shaped galls that develop on this plant are harvested and used in Ayurveda and Indian traditional medicine to make "karkatshringi", a herbal medicine used for the treatment of asthma and different disorders of respiratory tract. However, until now, the molecular mechanisms of action of "karkatshringi" and its chemical characterization are partially known. This study deals with the isolation and characterization of the active constituents from the methanolic extract of P. integerrima galls and it was also oriented to evaluate in vitro and in silico their potential enzymatic inhibitory activity against phosphodiesterase-1 (PDE1), a well-known enzyme involved in airway smooth muscle activity and airway inflammation. Our results showed that the methanolic extract of P. integerrima galls and some of its active constituents [naringenin (1) and 3,5,7,4'-tetrahydroxy-flavanone (2)] are able in vitro to inhibit PDE1 activity (59.20 ± 4.95%, 75.90 ± 5.90%, and 65.25 ± 5.25%, resp.) and demonstrate in silico an interesting interaction with this enzymatic site. Taken together, our results add new knowledge of chemical constituents responsible for the biological activity of P. integerrima and contextually legitimate the use of this plant in folk medicine.

No MeSH data available.


Related in: MedlinePlus

Superimposition of 1 and 2 (colored by green) and caffeine (colored by red) in the binding site of PDE1.
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fig5: Superimposition of 1 and 2 (colored by green) and caffeine (colored by red) in the binding site of PDE1.

Mentions: Phosphodiesterases (PDEs) are a family of enzymes that catalyze the breakdown of the second messengers cGMP and cAMP [36, 37]. The PDE family has been a focus of drug development in recent years, especially for cardiovascular and airway diseases because of the favorable effects that second messengers have in the vasculature which include increasing vasodilation and decreasing of smooth muscle cells proliferation [38–41]. Recent investigations have also demonstrated that systemic phosphodiesterase inhibitors administration could ameliorate bronchodilation and reduce airway inflammation [13, 14]. The results reported in Figure 2 indicate that methanol extract and compounds 1 and 2 possess a significant inhibitory activity against PDE1 enzyme (59.20 ± 4.95%, 75.90 ± 5.90%, and 65.25 ± 5.25% of PDE1, resp.) whereas compounds 3, 4, and 5 displayed only partial inhibitory activities (8.05 ± 3.05, 8.20 ± 3.20, and 10.70 ± 4.00%, resp.). The assay was performed in presence of positive control EDTA (85.05 ± 4.95 % of PDE1 inhibitory activity). Successively, we have investigated by docking studies the interaction of compounds 1 and 2 with the binding site of PDE1. Figure 3 shows the interaction of compound 1 (naringenin) with PDE1 enzyme binding pocket. These interactions including hydrogen bonds formed by Thr256 (with a distance of 3.02 Å and 2.97 Å) and Gln292 residues (with a distance of 2.57 Å) and hydrophobic interactions established by Tyr82, Asp241, Leu242, Asn244, Trp255, Tyr252, Ile259, Met280, Ser291 and Phe295 residues. Similar results were observed for compound 2. As shown in Figure 4, the flavonoid establishes hydrogen bonds formed by Thr256 (with a distance of 3.04 Å and 2.87 Å) and Gln292 (with a distance of 2.57 Å) residues and hydrophobic interactions established by Tyr82, Asp241, Leu242, Tyr252, Ile259, Met280, Ser291, and Phe295 residues. Moreover, in order to rationalize the binding mode of compounds 1 and 2, we have used the crystal structure of PDE1 linked to caffeine, a nonselective PDE inhibitor. The docking analysis was carried out through LIGPLOT+ version v.1.4.5, PyMOL version 1.7.2, and discovery studio visualizer version 4.0 software [42, 43]. The analysis of receptor ligand complex based on the hydrogen bond interaction and hydrophobic interaction shows that both compounds displayed a stronger interaction with PDE1 binding site compared with those of caffeine (Figure 5). In particular, the docking result of compounds 1 and 2 on PDE1 shows a binding energy of −7.9 kcal/mol and −7.8 kcal/mol, respectively, whereas the total energy was of −110 kcal/mol and −102 kcal/mol. These scores were much lower than that of caffeine (−6.3 kcal/mol; −73 kcal/mol) indicating that the two tested flavonoids possess higher PDE1 activity.


Phosphodiesterase-1 Inhibitory Activity of Two Flavonoids Isolated from Pistacia integerrima J. L. Stewart Galls.

Rauf A, Saleem M, Uddin G, Siddiqui BS, Khan H, Raza M, Hamid SZ, Khan A, Maione F, Mascolo N, De Feo V - Evid Based Complement Alternat Med (2015)

Superimposition of 1 and 2 (colored by green) and caffeine (colored by red) in the binding site of PDE1.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4402172&req=5

fig5: Superimposition of 1 and 2 (colored by green) and caffeine (colored by red) in the binding site of PDE1.
Mentions: Phosphodiesterases (PDEs) are a family of enzymes that catalyze the breakdown of the second messengers cGMP and cAMP [36, 37]. The PDE family has been a focus of drug development in recent years, especially for cardiovascular and airway diseases because of the favorable effects that second messengers have in the vasculature which include increasing vasodilation and decreasing of smooth muscle cells proliferation [38–41]. Recent investigations have also demonstrated that systemic phosphodiesterase inhibitors administration could ameliorate bronchodilation and reduce airway inflammation [13, 14]. The results reported in Figure 2 indicate that methanol extract and compounds 1 and 2 possess a significant inhibitory activity against PDE1 enzyme (59.20 ± 4.95%, 75.90 ± 5.90%, and 65.25 ± 5.25% of PDE1, resp.) whereas compounds 3, 4, and 5 displayed only partial inhibitory activities (8.05 ± 3.05, 8.20 ± 3.20, and 10.70 ± 4.00%, resp.). The assay was performed in presence of positive control EDTA (85.05 ± 4.95 % of PDE1 inhibitory activity). Successively, we have investigated by docking studies the interaction of compounds 1 and 2 with the binding site of PDE1. Figure 3 shows the interaction of compound 1 (naringenin) with PDE1 enzyme binding pocket. These interactions including hydrogen bonds formed by Thr256 (with a distance of 3.02 Å and 2.97 Å) and Gln292 residues (with a distance of 2.57 Å) and hydrophobic interactions established by Tyr82, Asp241, Leu242, Asn244, Trp255, Tyr252, Ile259, Met280, Ser291 and Phe295 residues. Similar results were observed for compound 2. As shown in Figure 4, the flavonoid establishes hydrogen bonds formed by Thr256 (with a distance of 3.04 Å and 2.87 Å) and Gln292 (with a distance of 2.57 Å) residues and hydrophobic interactions established by Tyr82, Asp241, Leu242, Tyr252, Ile259, Met280, Ser291, and Phe295 residues. Moreover, in order to rationalize the binding mode of compounds 1 and 2, we have used the crystal structure of PDE1 linked to caffeine, a nonselective PDE inhibitor. The docking analysis was carried out through LIGPLOT+ version v.1.4.5, PyMOL version 1.7.2, and discovery studio visualizer version 4.0 software [42, 43]. The analysis of receptor ligand complex based on the hydrogen bond interaction and hydrophobic interaction shows that both compounds displayed a stronger interaction with PDE1 binding site compared with those of caffeine (Figure 5). In particular, the docking result of compounds 1 and 2 on PDE1 shows a binding energy of −7.9 kcal/mol and −7.8 kcal/mol, respectively, whereas the total energy was of −110 kcal/mol and −102 kcal/mol. These scores were much lower than that of caffeine (−6.3 kcal/mol; −73 kcal/mol) indicating that the two tested flavonoids possess higher PDE1 activity.

Bottom Line: However, until now, the molecular mechanisms of action of "karkatshringi" and its chemical characterization are partially known.This study deals with the isolation and characterization of the active constituents from the methanolic extract of P. integerrima galls and it was also oriented to evaluate in vitro and in silico their potential enzymatic inhibitory activity against phosphodiesterase-1 (PDE1), a well-known enzyme involved in airway smooth muscle activity and airway inflammation.Our results showed that the methanolic extract of P. integerrima galls and some of its active constituents [naringenin (1) and 3,5,7,4'-tetrahydroxy-flavanone (2)] are able in vitro to inhibit PDE1 activity (59.20 ± 4.95%, 75.90 ± 5.90%, and 65.25 ± 5.25%, resp.) and demonstrate in silico an interesting interaction with this enzymatic site.

View Article: PubMed Central - PubMed

Affiliation: Institute of Chemical Sciences, University of Peshawar, Peshawar, Khyber Pakhtunkhwa 25120, Pakistan.

ABSTRACT
Pistacia integerrima is one of twenty species among the genus Pistacia. Long horn-shaped galls that develop on this plant are harvested and used in Ayurveda and Indian traditional medicine to make "karkatshringi", a herbal medicine used for the treatment of asthma and different disorders of respiratory tract. However, until now, the molecular mechanisms of action of "karkatshringi" and its chemical characterization are partially known. This study deals with the isolation and characterization of the active constituents from the methanolic extract of P. integerrima galls and it was also oriented to evaluate in vitro and in silico their potential enzymatic inhibitory activity against phosphodiesterase-1 (PDE1), a well-known enzyme involved in airway smooth muscle activity and airway inflammation. Our results showed that the methanolic extract of P. integerrima galls and some of its active constituents [naringenin (1) and 3,5,7,4'-tetrahydroxy-flavanone (2)] are able in vitro to inhibit PDE1 activity (59.20 ± 4.95%, 75.90 ± 5.90%, and 65.25 ± 5.25%, resp.) and demonstrate in silico an interesting interaction with this enzymatic site. Taken together, our results add new knowledge of chemical constituents responsible for the biological activity of P. integerrima and contextually legitimate the use of this plant in folk medicine.

No MeSH data available.


Related in: MedlinePlus