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Molecular Mechanism Underlying the Action of Substituted Pro-Gly Dipeptide Noopept.

Vakhitova YV, Sadovnikov SV, Borisevich SS, Ostrovskaya RU, A Gudasheva T, Seredenin SB - Acta Naturae (2016 Jan-Mar)

Bottom Line: Piracetam (1 mM) failed to affect significantly any of the TF under study.The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2.The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.

View Article: PubMed Central - PubMed

Affiliation: State Zakusov Institute of Pharmacology , Baltiyskaya Str., 8, 125315, Moscow, Russia ; Institute of Biochemistry and Genetics of Ufa Scientific Centre RAS, Prospekt Oktyabrya, 71, 450065 , Ufa, Russia.

ABSTRACT
This study was performed in order to reveal the effect of Noopept (ethyl ester of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding activity of transcriptional factors (TF) in HEK293 cells transiently transfected with luciferase reporter constructs containing sequences for CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (10 μM) was shown to increase the DNA-binding activity of HIF-1 only, while lacking the ability to affect that of CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. Noopept provoked an additional increase in the DNA-binding activity of HIF-1 when applied in conditions of CoCl2-induced HIF- 1 stabilization. The degree of this HIF-positive effect of Noopept was shown to be concentration-dependent. Piracetam (1 mM) failed to affect significantly any of the TF under study. The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2. Taking into account the important role of the genes activated by HIF-1 in the formation of an adaptive response to hypoxia, data on the ability of Noopept to provoke a selective increase in the DNA-binding activity of HIF-1 explain the wide spectrum of neurochemical and pharmacological effects of Noopept revealed before. The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.

No MeSH data available.


Related in: MedlinePlus

Results of molecular docking: location of ligands in the active site of prolylhydroxylase (hydrogen bonds are shown in dashed line)
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Figure 5: Results of molecular docking: location of ligands in the active site of prolylhydroxylase (hydrogen bonds are shown in dashed line)

Mentions: According to the results of the molecular docking, Noopept andL-isomer of N-phenylacetyl-Pro binds to the active site ofprolyl hydroxylase at a level of efficiency comparable with that of RA2LL-isomer (Table).The qualitative effectiveness of the ligand is estimated as high. L-stereoisomer of N-phenylacetyl-Pro forms hydrogen bonds with Arg383 and Tyr329in the active site of the enzyme, and the PA2L molecule is coordinated byoxygens around the Fe atom(Fig. 5).It should be underlinedthat the pharmacologically inactive Disomer of Noopept has alower binding energy. Thus, it can be assumed that Noopept and its metabolite,Lisomer of N- phenylacetyl-Pro, may bind to the active site ofprolyl hydroxylase 2 and, probably, inhibit its enzymatic activity. Apparently,the final conclusion requires further experimental study of the effect ofNoopept and its metabolite on the activity of prolyl hydroxylase. Possibleinteraction of Noopept with asparagine hydroxylase also requires additionalstudies.


Molecular Mechanism Underlying the Action of Substituted Pro-Gly Dipeptide Noopept.

Vakhitova YV, Sadovnikov SV, Borisevich SS, Ostrovskaya RU, A Gudasheva T, Seredenin SB - Acta Naturae (2016 Jan-Mar)

Results of molecular docking: location of ligands in the active site of prolylhydroxylase (hydrogen bonds are shown in dashed line)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837574&req=5

Figure 5: Results of molecular docking: location of ligands in the active site of prolylhydroxylase (hydrogen bonds are shown in dashed line)
Mentions: According to the results of the molecular docking, Noopept andL-isomer of N-phenylacetyl-Pro binds to the active site ofprolyl hydroxylase at a level of efficiency comparable with that of RA2LL-isomer (Table).The qualitative effectiveness of the ligand is estimated as high. L-stereoisomer of N-phenylacetyl-Pro forms hydrogen bonds with Arg383 and Tyr329in the active site of the enzyme, and the PA2L molecule is coordinated byoxygens around the Fe atom(Fig. 5).It should be underlinedthat the pharmacologically inactive Disomer of Noopept has alower binding energy. Thus, it can be assumed that Noopept and its metabolite,Lisomer of N- phenylacetyl-Pro, may bind to the active site ofprolyl hydroxylase 2 and, probably, inhibit its enzymatic activity. Apparently,the final conclusion requires further experimental study of the effect ofNoopept and its metabolite on the activity of prolyl hydroxylase. Possibleinteraction of Noopept with asparagine hydroxylase also requires additionalstudies.

Bottom Line: Piracetam (1 mM) failed to affect significantly any of the TF under study.The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2.The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.

View Article: PubMed Central - PubMed

Affiliation: State Zakusov Institute of Pharmacology , Baltiyskaya Str., 8, 125315, Moscow, Russia ; Institute of Biochemistry and Genetics of Ufa Scientific Centre RAS, Prospekt Oktyabrya, 71, 450065 , Ufa, Russia.

ABSTRACT
This study was performed in order to reveal the effect of Noopept (ethyl ester of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding activity of transcriptional factors (TF) in HEK293 cells transiently transfected with luciferase reporter constructs containing sequences for CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (10 μM) was shown to increase the DNA-binding activity of HIF-1 only, while lacking the ability to affect that of CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. Noopept provoked an additional increase in the DNA-binding activity of HIF-1 when applied in conditions of CoCl2-induced HIF- 1 stabilization. The degree of this HIF-positive effect of Noopept was shown to be concentration-dependent. Piracetam (1 mM) failed to affect significantly any of the TF under study. The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2. Taking into account the important role of the genes activated by HIF-1 in the formation of an adaptive response to hypoxia, data on the ability of Noopept to provoke a selective increase in the DNA-binding activity of HIF-1 explain the wide spectrum of neurochemical and pharmacological effects of Noopept revealed before. The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.

No MeSH data available.


Related in: MedlinePlus