Sandbox Reserved 957 - Revision history

Michael Pierrelee at 23:12, 9 January 2015

Michael Pierrelee — Fri, 09 Jan 2015 23:12:22 GMT

←Older revision		Revision as of 23:12, 9 January 2015
Line 7:		Line 7:
	There are 11 families of PDE (from 1 to 9), there is 21 genes for PDE which code 60 different PDE. For the PDE5A, the only PDE5 subcategory, there are 4 isoforms but their catalytic domain is the same <ref>Byung-Je Sung, Kwang Yeon Hwang, Young Ho Jeon, Jae Il Lee, Yong-Seok Heo, Jin Hwan Kim, Jinho Moon, Jung Min Yoon, Young-Lan Hyun, Eunmi Kim, Sung Jin Eum, Sam-Yong Park, Jie-Oh Lee, Tae Gyu Lee, Seonggu Ro & Joong Myung Cho, Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules, NATURE, VOL 425, 4 SEPTEMBER 2003</ref>.<br \>		There are 11 families of PDE (from 1 to 9), there is 21 genes for PDE which code 60 different PDE. For the PDE5A, the only PDE5 subcategory, there are 4 isoforms but their catalytic domain is the same <ref>Byung-Je Sung, Kwang Yeon Hwang, Young Ho Jeon, Jae Il Lee, Yong-Seok Heo, Jin Hwan Kim, Jinho Moon, Jung Min Yoon, Young-Lan Hyun, Eunmi Kim, Sung Jin Eum, Sam-Yong Park, Jie-Oh Lee, Tae Gyu Lee, Seonggu Ro & Joong Myung Cho, Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules, NATURE, VOL 425, 4 SEPTEMBER 2003</ref>.<br \>
	The catalytic reaction is the hydrolysis of guanosine cyclic monophosphate into linear guanosine monophosphate. This cGMP-specific enzyme have 3 domains (from N terminal to C terminal) : GAF A, GAF B and a conserved catalytic domain regard to other PDEs of the family. Only cGMP can bind GAF A or GAF B and it stimulates the hydrolysis.<br \>		The catalytic reaction is the hydrolysis of guanosine cyclic monophosphate into linear guanosine monophosphate. This cGMP-specific enzyme have 3 domains (from N terminal to C terminal) : GAF A, GAF B and a conserved catalytic domain regard to other PDEs of the family. Only cGMP can bind GAF A or GAF B and it stimulates the hydrolysis.<br \>
-	We study here the PDE5A catalytic fragment formed of amino acid residues from the 535th to the 860th <ref>~~PDB~~</ref>. In the inhibition, we talk about the Sildenafil mostly, because it's the most known (active ingredient in the Viagra®).<br \>	+	We study here the PDE5A catalytic fragment formed of amino acid residues from the 535th to the 860th <ref>http://www.rcsb.org/pdb/explore.do?structureId=2H40</ref>. In the inhibition, we talk about the Sildenafil mostly, because it's the most known (active ingredient in the Viagra®).<br \>
	Problem in the PBD files: N-loop (from the 788th to the 881th residues) is not complete.		Problem in the PBD files: N-loop (from the 788th to the 881th residues) is not complete.

Michael Pierrelee at 23:08, 9 January 2015

Michael Pierrelee — Fri, 09 Jan 2015 23:08:19 GMT

←Older revision		Revision as of 23:08, 9 January 2015
Line 4:		Line 4:
	Sekiguchi M, Hoshizaki H, Adachi H, Ohshima S, Taniguchi K, Kurabayashi M. Effects of antiplatelet agents on subacute thrombosis and restenosis after successful coronary stenting: a randomized comparison of ticlopidine and cilostazol. Circ J 68: 610–614, 2004.		Sekiguchi M, Hoshizaki H, Adachi H, Ohshima S, Taniguchi K, Kurabayashi M. Effects of antiplatelet agents on subacute thrombosis and restenosis after successful coronary stenting: a randomized comparison of ticlopidine and cilostazol. Circ J 68: 610–614, 2004.
	Sopory S, Kaur T, Visweswariah SS. The cGMP-binding, cGMPspecific phosphodiesterase (PDE5): intestinal cell expression, regulation and role in fluid secretion. Cell Signal 16: 681–692, 2004.<br \>		Sopory S, Kaur T, Visweswariah SS. The cGMP-binding, cGMPspecific phosphodiesterase (PDE5): intestinal cell expression, regulation and role in fluid secretion. Cell Signal 16: 681–692, 2004.<br \>
-	Zhu B, Strada S, Stevens T. Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 289: L196–L206, 2005.<br \></ref> and platelets and Corpus Cavernosum. In particular, it is implied in the NO pathway of penile erection and so in the Erectile Dysfunction (ED) <ref>~~[22]~~</ref>.<br \>	+	Zhu B, Strada S, Stevens T. Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 289: L196–L206, 2005.<br \></ref> and platelets and Corpus Cavernosum. In particular, it is implied in the NO pathway of penile erection and so in the Erectile Dysfunction (ED) <ref>JD Corbin, Mechanisms of action of PDE5 inhibition in erectile dysfunction, International Journal of Impotence Research (2004) 16, S4–S7</ref>.<br \>
	There are 11 families of PDE (from 1 to 9), there is 21 genes for PDE which code 60 different PDE. For the PDE5A, the only PDE5 subcategory, there are 4 isoforms but their catalytic domain is the same <ref>Byung-Je Sung, Kwang Yeon Hwang, Young Ho Jeon, Jae Il Lee, Yong-Seok Heo, Jin Hwan Kim, Jinho Moon, Jung Min Yoon, Young-Lan Hyun, Eunmi Kim, Sung Jin Eum, Sam-Yong Park, Jie-Oh Lee, Tae Gyu Lee, Seonggu Ro & Joong Myung Cho, Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules, NATURE, VOL 425, 4 SEPTEMBER 2003</ref>.<br \>		There are 11 families of PDE (from 1 to 9), there is 21 genes for PDE which code 60 different PDE. For the PDE5A, the only PDE5 subcategory, there are 4 isoforms but their catalytic domain is the same <ref>Byung-Je Sung, Kwang Yeon Hwang, Young Ho Jeon, Jae Il Lee, Yong-Seok Heo, Jin Hwan Kim, Jinho Moon, Jung Min Yoon, Young-Lan Hyun, Eunmi Kim, Sung Jin Eum, Sam-Yong Park, Jie-Oh Lee, Tae Gyu Lee, Seonggu Ro & Joong Myung Cho, Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules, NATURE, VOL 425, 4 SEPTEMBER 2003</ref>.<br \>
	The catalytic reaction is the hydrolysis of guanosine cyclic monophosphate into linear guanosine monophosphate. This cGMP-specific enzyme have 3 domains (from N terminal to C terminal) : GAF A, GAF B and a conserved catalytic domain regard to other PDEs of the family. Only cGMP can bind GAF A or GAF B and it stimulates the hydrolysis.<br \>		The catalytic reaction is the hydrolysis of guanosine cyclic monophosphate into linear guanosine monophosphate. This cGMP-specific enzyme have 3 domains (from N terminal to C terminal) : GAF A, GAF B and a conserved catalytic domain regard to other PDEs of the family. Only cGMP can bind GAF A or GAF B and it stimulates the hydrolysis.<br \>
Line 91:		Line 91:
	As it is written over, there are 2 regulatory domains (GAF A and GAF B). In cGMP pathway, PDE5 allows a negative feedback of the molecule: first, in presence of cGMP, it binds GAF A which stimulates the catalysis in the active site, and vice versa. Moreover, cGMP actives PKG which phophorylates PDE5, that is stimulated by the presence of cGMP on the GAF A or/and the active site. If the protein is not binding with cGMP but it is phophorylated, that stimulates the binding of cGMP on GAF A and the catalytic site. So cGMP presence overstimulates the catalysis <ref>Okada D, Asakawa S. Allosteric activation of cGMP-specific, cGMP-binding phosphodiesterase (PDE5) by cGMP. Biochemistry 41: 9672–9679, 2002		As it is written over, there are 2 regulatory domains (GAF A and GAF B). In cGMP pathway, PDE5 allows a negative feedback of the molecule: first, in presence of cGMP, it binds GAF A which stimulates the catalysis in the active site, and vice versa. Moreover, cGMP actives PKG which phophorylates PDE5, that is stimulated by the presence of cGMP on the GAF A or/and the active site. If the protein is not binding with cGMP but it is phophorylated, that stimulates the binding of cGMP on GAF A and the catalytic site. So cGMP presence overstimulates the catalysis <ref>Okada D, Asakawa S. Allosteric activation of cGMP-specific, cGMP-binding phosphodiesterase (PDE5) by cGMP. Biochemistry 41: 9672–9679, 2002
	Weber G. Energetics of ligand binding to protein. Adv Protein Chem 29: 1–83, 1975.		Weber G. Energetics of ligand binding to protein. Adv Protein Chem 29: 1–83, 1975.
-	Bessay EP, Blount MA, Zoraghi R, Beasley A, Grimes KA, Francis SH, Corbin JD. Phosphorylation increases affinity of the phosphodiesterase-5 catalytic site for tadalafil. J Pharmacol Exp Ther 325: 62–68, 2008.</ref>. And it also increase inhibitor's affinity<ref>Bessay EP, Zoraghi R, Blount MA, Grimes KA, Beasley A, Francis SH, Corbin JD. Phosphorylation of phosphodiesterase-5 is promoted by a conformational change induced by sildenafil, vardenafil, or tadalafil. Front Biosci 12: 1899–1910, 2007.</ref> and without cGMP, inhibitor don’t bind the PDE5 <ref>~~[22]~~</ref>.<br \>	+	Bessay EP, Blount MA, Zoraghi R, Beasley A, Grimes KA, Francis SH, Corbin JD. Phosphorylation increases affinity of the phosphodiesterase-5 catalytic site for tadalafil. J Pharmacol Exp Ther 325: 62–68, 2008.</ref>. And it also increase inhibitor's affinity<ref>Bessay EP, Zoraghi R, Blount MA, Grimes KA, Beasley A, Francis SH, Corbin JD. Phosphorylation of phosphodiesterase-5 is promoted by a conformational change induced by sildenafil, vardenafil, or tadalafil. Front Biosci 12: 1899–1910, 2007.</ref> and without cGMP, inhibitor don’t bind the PDE5 <ref>JD Corbin, Mechanisms of action of PDE5 inhibition in erectile dysfunction, International Journal of Impotence Research (2004) 16, S4–S7</ref>.<br \>

	== The NO Pathway ==		== The NO Pathway ==

Michael Pierrelee at 23:06, 9 January 2015

Michael Pierrelee — Fri, 09 Jan 2015 23:06:54 GMT

(Difference between revisions)

Michael Pierrelee at 23:00, 9 January 2015

Michael Pierrelee — Fri, 09 Jan 2015 23:00:30 GMT

←Older revision		Revision as of 23:00, 9 January 2015
Line 99:		Line 99:
	Okada D, Asakawa S. Allosteric activation of cGMP-specific, cGMP-binding phosphodiesterase (PDE5) by cGMP. Biochemistry 41: 9672–9679, 2002		Okada D, Asakawa S. Allosteric activation of cGMP-specific, cGMP-binding phosphodiesterase (PDE5) by cGMP. Biochemistry 41: 9672–9679, 2002
	Weber G. Energetics of ligand binding to protein. Adv Protein Chem 29: 1–83, 1975.		Weber G. Energetics of ligand binding to protein. Adv Protein Chem 29: 1–83, 1975.
-	Bessay EP, Blount MA, Zoraghi R, Beasley A, Grimes KA, Francis SH, Corbin JD. Phosphorylation increases affinity of the phosphodiesterase-5 catalytic site for tadalafil. J Pharmacol Exp Ther 325: 62–68, 2008.	+	Bessay EP, Blount MA, Zoraghi R, Beasley A, Grimes KA, Francis SH, Corbin JD. Phosphorylation increases affinity of the phosphodiesterase-5 catalytic site for tadalafil. J Pharmacol Exp Ther 325: 62–68, 2008.<br>
	[20]:		[20]:
-	Bessay EP, Zoraghi R, Blount MA, Grimes KA, Beasley A, Francis SH, Corbin JD. Phosphorylation of phosphodiesterase-5 is promoted by a conformational change induced by sildenafil, vardenafil, or tadalafil. Front Biosci 12: 1899–1910, 2007.	+	Bessay EP, Zoraghi R, Blount MA, Grimes KA, Beasley A, Francis SH, Corbin JD. Phosphorylation of phosphodiesterase-5 is promoted by a conformational change induced by sildenafil, vardenafil, or tadalafil. Front Biosci 12: 1899–1910, 2007.<br>
	[21]:		[21]:
-	Huanchen Wang, Yudong Liu, Qing Huai, Jiwen Cai, Roya Zoraghi, Sharron H. Francis, Jackie D. Corbin, Howard Robinson, Zhongcheng Xin, Guiting Lin, and Hengming Ke Zhongcheng Xin, Guiting Lin and Hengming Jackie D. Corbin, Howard Robinson, Jiwen Cai, Roya Zoraghi, Sharron H. Francis, Huanchen Wang, Yudong Liu, Qing Huai, Multiple Conformations of Phosphodiesterase-5: implications for enzyme function and drug development, The Journal of Biological Chemistry VOL. 281, NO. 30, pp. 21469–21479, July 28, 2006	+	Huanchen Wang, Yudong Liu, Qing Huai, Jiwen Cai, Roya Zoraghi, Sharron H. Francis, Jackie D. Corbin, Howard Robinson, Zhongcheng Xin, Guiting Lin, and Hengming Ke Zhongcheng Xin, Guiting Lin and Hengming Jackie D. Corbin, Howard Robinson, Jiwen Cai, Roya Zoraghi, Sharron H. Francis, Huanchen Wang, Yudong Liu, Qing Huai, Multiple Conformations of Phosphodiesterase-5: implications for enzyme function and drug development, The Journal of Biological Chemistry VOL. 281, NO. 30, pp. 21469–21479, July 28, 2006<br>
	[22]:		[22]:
-	JD Corbin, Mechanisms of action of PDE5 inhibition in erectile dysfunction, International Journal of Impotence Research (2004) 16, S4–S7	+	JD Corbin, Mechanisms of action of PDE5 inhibition in erectile dysfunction, International Journal of Impotence Research (2004) 16, S4–S7<br>
-	[23]: PDB	+	[23]: PDB<br>
-	[24]: ~~article 2003~~	+	[24]:
-	Byung-Je Sung, Kwang Yeon Hwang, Young Ho Jeon, Jae Il Lee, Yong-Seok Heo, Jin Hwan Kim, Jinho Moon, Jung Min Yoon, Young-Lan Hyun, Eunmi Kim, Sung Jin Eum, Sam-Yong Park, Jie-Oh Lee, Tae Gyu Lee, Seonggu Ro & Joong Myung Cho, Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules, NATURE, VOL 425, 4 SEPTEMBER 2003	+	Byung-Je Sung, Kwang Yeon Hwang, Young Ho Jeon, Jae Il Lee, Yong-Seok Heo, Jin Hwan Kim, Jinho Moon, Jung Min Yoon, Young-Lan Hyun, Eunmi Kim, Sung Jin Eum, Sam-Yong Park, Jie-Oh Lee, Tae Gyu Lee, Seonggu Ro & Joong Myung Cho, Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules, NATURE, VOL 425, 4 SEPTEMBER 2003<br>
	[26]:		[26]:
-	Jeffrey, P. D. et al. Mechanism of CDK activation revealed by the structure of a cyclinA–CDK2 complex. Nature 376, 313–320 (1995).	+	Jeffrey, P. D. et al. Mechanism of CDK activation revealed by the structure of a cyclinA–CDK2 complex. Nature 376, 313–320 (1995).<br>
-	Nikolov, D. B. et al. Crystal structure of a TFIIB-TBP-TATA-element ternary complex. Nature 377, 119–128 (1995).	+	Nikolov, D. B. et al. Crystal structure of a TFIIB-TBP-TATA-element ternary complex. Nature 377, 119–128 (1995).<br>
	[25]: article 1999		[25]: article 1999
-	Tamara L. Fink, Sharron H. Francis, Alfreda Beasley, Kennard A. Grimes, and Jackie D. Corbin, Expression of an Active, Monomeric Catalytic Domain of the cGMP-binding cGMP-specific Phosphodiesterase (PDE5), The Journal Of Biological Chemistry, Vol. 274, No. 49, Issue of December 3, pp. 34613–34620, 1999.	+	Tamara L. Fink, Sharron H. Francis, Alfreda Beasley, Kennard A. Grimes, and Jackie D. Corbin, Expression of an Active, Monomeric Catalytic Domain of the cGMP-binding cGMP-specific Phosphodiesterase (PDE5), The Journal Of Biological Chemistry, Vol. 274, No. 49, Issue of December 3, pp. 34613–34620, 1999.<br>

Michael Pierrelee at 22:59, 9 January 2015

Michael Pierrelee — Fri, 09 Jan 2015 22:59:05 GMT

(Difference between revisions)

Michael Pierrelee at 22:53, 9 January 2015

Michael Pierrelee — Fri, 09 Jan 2015 22:53:14 GMT

←Older revision		Revision as of 22:53, 9 January 2015
Line 6:		Line 6:
	We study here the PDE5A catalytic fragment formed of amino acid residues from the 535th to the 860th <ref>[23]</ref>. In the inhibition, we talk about the Sildenafil mostly, because it's the most known (active ingredient in the Viagra®).<br \>		We study here the PDE5A catalytic fragment formed of amino acid residues from the 535th to the 860th <ref>[23]</ref>. In the inhibition, we talk about the Sildenafil mostly, because it's the most known (active ingredient in the Viagra®).<br \>
	Problem in the PBD files: N-loop (from the 788th to the 881th residues) is not complete.		Problem in the PBD files: N-loop (from the 788th to the 881th residues) is not complete.
-		+	qsd
	== Structure of catalytic site ==		== Structure of catalytic site ==
	The only catalytic fragment is effective, so the regulations sites and the dimerization to a trimeric enzyme are useless for the catalytic activity. Moreover, this catalytic moiety has the same activity that the wild-type enzyme, so maybe the enzyme is monomeric in the cell <ref>[24]</ref>.		The only catalytic fragment is effective, so the regulations sites and the dimerization to a trimeric enzyme are useless for the catalytic activity. Moreover, this catalytic moiety has the same activity that the wild-type enzyme, so maybe the enzyme is monomeric in the cell <ref>[24]</ref>.

Michael Pierrelee at 22:49, 9 January 2015

Michael Pierrelee — Fri, 09 Jan 2015 22:49:15 GMT

←Older revision		Revision as of 22:49, 9 January 2015
Line 44:		Line 44:
	== Inhibition ==		== Inhibition ==
	In the treatment erection dysfunction, the inhibitors Sildenafil, Vardenafil and Tadalafil are used, like in the pulmonary hypertension<ref>[6]</ref>. Sildenafil may cure sleeping trouble after a intercontinental travel <ref>[11]</ref>, may help to recover neural liaisons after an injury (the motor function<ref>[12]</ref> and the sensory motor function<ref>[13]</ref>) and can be vascular effects.<br \>		In the treatment erection dysfunction, the inhibitors Sildenafil, Vardenafil and Tadalafil are used, like in the pulmonary hypertension<ref>[6]</ref>. Sildenafil may cure sleeping trouble after a intercontinental travel <ref>[11]</ref>, may help to recover neural liaisons after an injury (the motor function<ref>[12]</ref> and the sensory motor function<ref>[13]</ref>) and can be vascular effects.<br \>
-	<gallery ~~caption="The Sildenafil"~~>Image:Sildenafil.jpg\|Sildenafil Inhibitor, R1 in blue, R2 in green and R3 in red	+	<gallery>Image:Sildenafil.jpg\|500px\|Sildenafil Inhibitor, R1 in blue, R2 in green and R3 in red
-	Image:Sildenafilspace.jpg\|Sildenafil Inhibitor in the space in the enzyme</gallery>	+	Image:Sildenafilspace.jpg\|500px\|Sildenafil Inhibitor in the space in the enzyme</gallery>

	* PDE5 inhibitors might help physical condition in Duchene muscular dystrophy<ref>[14]</ref>, improve of cognitive function <ref>[9]</ref>and have antidepressant effect<ref>[10]</ref> , also they might have an artero<ref>[15]</ref> and endothelial cell protective effect<ref>[16]</ref> so they have cardiac protection effect<ref>[17]</ref> (controversial, cf. clinical trial “RELAX”), finally they slow tumer cell growth (Tadalafil-like)<ref>[18]</ref><br \>		* PDE5 inhibitors might help physical condition in Duchene muscular dystrophy<ref>[14]</ref>, improve of cognitive function <ref>[9]</ref>and have antidepressant effect<ref>[10]</ref> , also they might have an artero<ref>[15]</ref> and endothelial cell protective effect<ref>[16]</ref> so they have cardiac protection effect<ref>[17]</ref> (controversial, cf. clinical trial “RELAX”), finally they slow tumer cell growth (Tadalafil-like)<ref>[18]</ref><br \>
Line 54:		Line 54:
	* 3 parts (R1: pyrazolopyrimidinone group; R2: ethoxyphenyl; R3: methylpiperazine)<br \>		* 3 parts (R1: pyrazolopyrimidinone group; R2: ethoxyphenyl; R3: methylpiperazine)<br \>
	* It is bound near Metallic ions but does not interact with them.<br \>		* It is bound near Metallic ions but does not interact with them.<br \>
-	~~{{Clr}}~~	+
	Binding amino acid for the Sildenafil:<br \>		Binding amino acid for the Sildenafil:<br \>
	* R1 group have contacts with <scene name='60/604476/R1-1/1'>Gln817</scene> (2 hydrogen bounds, so it increases Sildenafil affinity), <scene name='60/604476/R1-1/1'>Phe820</scene> (Sildenafil stacks against it), <scene name='60/604476/R1-1/1'>Try612</scene> (hydrogen bound so it increases Sildenafil affinity <ref>[24]</ref>), <scene name='60/604476/R1-1/1'>Leu765</scene> and <scene name='60/604476/R1-1/1'>Ala767</scene> <ref>[21]</ref>. And there is hydrophobic interactions between the pyrazol ring and residues <scene name='60/604476/R1-2/1'>Val782, Leu785, Tyr612 and Phe820</scene> <ref>[24]</ref>.<br \>		* R1 group have contacts with <scene name='60/604476/R1-1/1'>Gln817</scene> (2 hydrogen bounds, so it increases Sildenafil affinity), <scene name='60/604476/R1-1/1'>Phe820</scene> (Sildenafil stacks against it), <scene name='60/604476/R1-1/1'>Try612</scene> (hydrogen bound so it increases Sildenafil affinity <ref>[24]</ref>), <scene name='60/604476/R1-1/1'>Leu765</scene> and <scene name='60/604476/R1-1/1'>Ala767</scene> <ref>[21]</ref>. And there is hydrophobic interactions between the pyrazol ring and residues <scene name='60/604476/R1-2/1'>Val782, Leu785, Tyr612 and Phe820</scene> <ref>[24]</ref>.<br \>
Line 75:		Line 75:
	</StructureSection>		</StructureSection>
	== References ==		== References ==
-	<references/>
	[1] Francis SH, Zoraghi R, Kotera J, Ke H, Bessay EP, Blount MA, Corbin JD. Phosphodiesterase-5: molecular characteristics relating to structure, function, and regulation. In: Cyclic Nucleotide Phosphodiesterases in Health and Disease, edited by Beavo JA, Houslay MD, Francis SH. Boca Raton, FL: CRC, 2006, p. 131–164.<br \>		[1] Francis SH, Zoraghi R, Kotera J, Ke H, Bessay EP, Blount MA, Corbin JD. Phosphodiesterase-5: molecular characteristics relating to structure, function, and regulation. In: Cyclic Nucleotide Phosphodiesterases in Health and Disease, edited by Beavo JA, Houslay MD, Francis SH. Boca Raton, FL: CRC, 2006, p. 131–164.<br \>
	Sekiguchi M, Hoshizaki H, Adachi H, Ohshima S, Taniguchi K, Kurabayashi M. Effects of antiplatelet agents on subacute thrombosis and restenosis after successful coronary stenting: a randomized comparison of ticlopidine and cilostazol. Circ J 68: 610–614, 2004.		Sekiguchi M, Hoshizaki H, Adachi H, Ohshima S, Taniguchi K, Kurabayashi M. Effects of antiplatelet agents on subacute thrombosis and restenosis after successful coronary stenting: a randomized comparison of ticlopidine and cilostazol. Circ J 68: 610–614, 2004.
	Sopory S, Kaur T, Visweswariah SS. The cGMP-binding, cGMPspecific phosphodiesterase (PDE5): intestinal cell expression, regulation and role in fluid secretion. Cell Signal 16: 681–692, 2004.<br \>		Sopory S, Kaur T, Visweswariah SS. The cGMP-binding, cGMPspecific phosphodiesterase (PDE5): intestinal cell expression, regulation and role in fluid secretion. Cell Signal 16: 681–692, 2004.<br \>
	Zhu B, Strada S, Stevens T. Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 289: L196–L206, 2005.<br \>		Zhu B, Strada S, Stevens T. Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 289: L196–L206, 2005.<br \>
		+	<references/>

Michael Pierrelee at 22:48, 9 January 2015

Michael Pierrelee — Fri, 09 Jan 2015 22:48:43 GMT

←Older revision		Revision as of 22:48, 9 January 2015
Line 44:		Line 44:
	== Inhibition ==		== Inhibition ==
	In the treatment erection dysfunction, the inhibitors Sildenafil, Vardenafil and Tadalafil are used, like in the pulmonary hypertension<ref>[6]</ref>. Sildenafil may cure sleeping trouble after a intercontinental travel <ref>[11]</ref>, may help to recover neural liaisons after an injury (the motor function<ref>[12]</ref> and the sensory motor function<ref>[13]</ref>) and can be vascular effects.<br \>		In the treatment erection dysfunction, the inhibitors Sildenafil, Vardenafil and Tadalafil are used, like in the pulmonary hypertension<ref>[6]</ref>. Sildenafil may cure sleeping trouble after a intercontinental travel <ref>[11]</ref>, may help to recover neural liaisons after an injury (the motor function<ref>[12]</ref> and the sensory motor function<ref>[13]</ref>) and can be vascular effects.<br \>
-	<gallery>Image:Sildenafil.jpg~~\|500px~~\|Sildenafil Inhibitor, R1 in blue, R2 in green and R3 in red	+	<gallery caption="The Sildenafil">Image:Sildenafil.jpg\|Sildenafil Inhibitor, R1 in blue, R2 in green and R3 in red
-	Image:Sildenafilspace.jpg~~\|500px~~\|Sildenafil Inhibitor in the space in the enzyme</gallery>	+	Image:Sildenafilspace.jpg\|Sildenafil Inhibitor in the space in the enzyme</gallery>

	* PDE5 inhibitors might help physical condition in Duchene muscular dystrophy<ref>[14]</ref>, improve of cognitive function <ref>[9]</ref>and have antidepressant effect<ref>[10]</ref> , also they might have an artero<ref>[15]</ref> and endothelial cell protective effect<ref>[16]</ref> so they have cardiac protection effect<ref>[17]</ref> (controversial, cf. clinical trial “RELAX”), finally they slow tumer cell growth (Tadalafil-like)<ref>[18]</ref><br \>		* PDE5 inhibitors might help physical condition in Duchene muscular dystrophy<ref>[14]</ref>, improve of cognitive function <ref>[9]</ref>and have antidepressant effect<ref>[10]</ref> , also they might have an artero<ref>[15]</ref> and endothelial cell protective effect<ref>[16]</ref> so they have cardiac protection effect<ref>[17]</ref> (controversial, cf. clinical trial “RELAX”), finally they slow tumer cell growth (Tadalafil-like)<ref>[18]</ref><br \>
Line 54:		Line 54:
	* 3 parts (R1: pyrazolopyrimidinone group; R2: ethoxyphenyl; R3: methylpiperazine)<br \>		* 3 parts (R1: pyrazolopyrimidinone group; R2: ethoxyphenyl; R3: methylpiperazine)<br \>
	* It is bound near Metallic ions but does not interact with them.<br \>		* It is bound near Metallic ions but does not interact with them.<br \>
-		+	{{Clr}}
	Binding amino acid for the Sildenafil:<br \>		Binding amino acid for the Sildenafil:<br \>
	* R1 group have contacts with <scene name='60/604476/R1-1/1'>Gln817</scene> (2 hydrogen bounds, so it increases Sildenafil affinity), <scene name='60/604476/R1-1/1'>Phe820</scene> (Sildenafil stacks against it), <scene name='60/604476/R1-1/1'>Try612</scene> (hydrogen bound so it increases Sildenafil affinity <ref>[24]</ref>), <scene name='60/604476/R1-1/1'>Leu765</scene> and <scene name='60/604476/R1-1/1'>Ala767</scene> <ref>[21]</ref>. And there is hydrophobic interactions between the pyrazol ring and residues <scene name='60/604476/R1-2/1'>Val782, Leu785, Tyr612 and Phe820</scene> <ref>[24]</ref>.<br \>		* R1 group have contacts with <scene name='60/604476/R1-1/1'>Gln817</scene> (2 hydrogen bounds, so it increases Sildenafil affinity), <scene name='60/604476/R1-1/1'>Phe820</scene> (Sildenafil stacks against it), <scene name='60/604476/R1-1/1'>Try612</scene> (hydrogen bound so it increases Sildenafil affinity <ref>[24]</ref>), <scene name='60/604476/R1-1/1'>Leu765</scene> and <scene name='60/604476/R1-1/1'>Ala767</scene> <ref>[21]</ref>. And there is hydrophobic interactions between the pyrazol ring and residues <scene name='60/604476/R1-2/1'>Val782, Leu785, Tyr612 and Phe820</scene> <ref>[24]</ref>.<br \>

Michael Pierrelee at 22:48, 9 January 2015

Michael Pierrelee — Fri, 09 Jan 2015 22:48:09 GMT

←Older revision		Revision as of 22:48, 9 January 2015
Line 76:		Line 76:
	== References ==		== References ==
	<references/>		<references/>
		+	[1] Francis SH, Zoraghi R, Kotera J, Ke H, Bessay EP, Blount MA, Corbin JD. Phosphodiesterase-5: molecular characteristics relating to structure, function, and regulation. In: Cyclic Nucleotide Phosphodiesterases in Health and Disease, edited by Beavo JA, Houslay MD, Francis SH. Boca Raton, FL: CRC, 2006, p. 131–164.<br \>
		+	Sekiguchi M, Hoshizaki H, Adachi H, Ohshima S, Taniguchi K, Kurabayashi M. Effects of antiplatelet agents on subacute thrombosis and restenosis after successful coronary stenting: a randomized comparison of ticlopidine and cilostazol. Circ J 68: 610–614, 2004.
		+	Sopory S, Kaur T, Visweswariah SS. The cGMP-binding, cGMPspecific phosphodiesterase (PDE5): intestinal cell expression, regulation and role in fluid secretion. Cell Signal 16: 681–692, 2004.<br \>
		+	Zhu B, Strada S, Stevens T. Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 289: L196–L206, 2005.<br \>

Michael Pierrelee at 22:46, 9 January 2015

Michael Pierrelee — Fri, 09 Jan 2015 22:46:20 GMT

←Older revision		Revision as of 22:46, 9 January 2015
Line 47:		Line 47:
	Image:Sildenafilspace.jpg\|500px\|Sildenafil Inhibitor in the space in the enzyme</gallery>		Image:Sildenafilspace.jpg\|500px\|Sildenafil Inhibitor in the space in the enzyme</gallery>

-	* PDE5 inhibitors might help physical condition in Duchene muscular dystrophy<ref>[14]</ref>, improve of cognitive function <ref>[9]</ref>and have antidepressant effect<ref>[10]</ref> , also they might have an artero<ref>[15]</ref> and endothelial cell protective effect<ref>[16]</ref> so they have cardiac protection effect<ref>[17]</ref> (controversial, cf. clinical trial “RELAX”), finally they slow tumer cell growth (Tadalafil-like)[18]<br \>	+	* PDE5 inhibitors might help physical condition in Duchene muscular dystrophy<ref>[14]</ref>, improve of cognitive function <ref>[9]</ref>and have antidepressant effect<ref>[10]</ref> , also they might have an artero<ref>[15]</ref> and endothelial cell protective effect<ref>[16]</ref> so they have cardiac protection effect<ref>[17]</ref> (controversial, cf. clinical trial “RELAX”), finally they slow tumer cell growth (Tadalafil-like)<ref>[18]</ref><br \>
	* There are other PDE5 inhibitors: IBMX, Icarisid II and Udenafil.<br \>		* There are other PDE5 inhibitors: IBMX, Icarisid II and Udenafil.<br \>
	* No interaction between the M site and the inhibitors<br \>		* No interaction between the M site and the inhibitors<br \>
Line 56:		Line 56:

	Binding amino acid for the Sildenafil:<br \>		Binding amino acid for the Sildenafil:<br \>
-	* R1 group have contacts with <scene name='60/604476/R1-1/1'>Gln817</scene> (2 hydrogen bounds, so it increases Sildenafil affinity), <scene name='60/604476/R1-1/1'>Phe820</scene> (Sildenafil stacks against it), <scene name='60/604476/R1-1/1'>Try612</scene> (hydrogen bound so it increases Sildenafil affinity [24]), <scene name='60/604476/R1-1/1'>Leu765</scene> and <scene name='60/604476/R1-1/1'>Ala767</scene> [21]. And there is hydrophobic interactions between the pyrazol ring and residues <scene name='60/604476/R1-2/1'>Val782, Leu785, Tyr612 and Phe820</scene> [24].<br \>	+	* R1 group have contacts with <scene name='60/604476/R1-1/1'>Gln817</scene> (2 hydrogen bounds, so it increases Sildenafil affinity), <scene name='60/604476/R1-1/1'>Phe820</scene> (Sildenafil stacks against it), <scene name='60/604476/R1-1/1'>Try612</scene> (hydrogen bound so it increases Sildenafil affinity <ref>[24]</ref>), <scene name='60/604476/R1-1/1'>Leu765</scene> and <scene name='60/604476/R1-1/1'>Ala767</scene> <ref>[21]</ref>. And there is hydrophobic interactions between the pyrazol ring and residues <scene name='60/604476/R1-2/1'>Val782, Leu785, Tyr612 and Phe820</scene> <ref>[24]</ref>.<br \>
	* R2 group is in the H pocket and has Van der Waals bounds with Val 782, Ala 783, Phe 786, Leu 804, Ile 813, Gln 817, Phe801. And interaction Pi-Pi between the phenyl ring and the Phe820.<br \>		* R2 group is in the H pocket and has Van der Waals bounds with Val 782, Ala 783, Phe 786, Leu 804, Ile 813, Gln 817, Phe801. And interaction Pi-Pi between the phenyl ring and the Phe820.<br \>
	* R3 group is in the L pocket and has contacts with <scene name='60/604476/662_804/1'>Asn 662, Ser 663, Tyr 664, Ile 665 (in the H-loop), Leu 804, Phe 801</scene>		* R3 group is in the L pocket and has contacts with <scene name='60/604476/662_804/1'>Asn 662, Ser 663, Tyr 664, Ile 665 (in the H-loop), Leu 804, Phe 801</scene>
-	* <scene name='60/604476/Gly659/2'>Gly659</scene> is modified by Sildenafil presence in PDE5, ϕ and φ angles are increased (from 76-105° to 104-109° for ϕ and from 3-22° to 139-141° for φ) and ω angle is not changed. [21]<br \>	+	* <scene name='60/604476/Gly659/2'>Gly659</scene> is modified by Sildenafil presence in PDE5, ϕ and φ angles are increased (from 76-105° to 104-109° for ϕ and from 3-22° to 139-141° for φ) and ω angle is not changed. <ref>[21]</ref><br \>

	H-loop:<br \>		H-loop:<br \>
	For each inhibitor, <scene name='60/604476/H_loop/1'>H-loop</scene> take a different and originally (comparatively to other PDEs) tertiary structure (and there are also minor modifications of <scene name='60/604476/N_loop/1'>the N-loop (788-811)</scene> ):<br \>		For each inhibitor, <scene name='60/604476/H_loop/1'>H-loop</scene> take a different and originally (comparatively to other PDEs) tertiary structure (and there are also minor modifications of <scene name='60/604476/N_loop/1'>the N-loop (788-811)</scene> ):<br \>
-	* For an unliganded PDE5, <scene name='60/604476/H_loop/1'>H-loop</scene> take a coil conformation. [21]<br \>	+	* For an unliganded PDE5, <scene name='60/604476/H_loop/1'>H-loop</scene> take a coil conformation. <ref>[21]</ref><br \>
-	* In case of Sildenafil binding, a turn and an 3ind10<scene name='60/604476/3-10helix/1'> helix (from 672 to 675)</scene> appear, and <scene name='60/604476/668_676/1'>from 668 to 676</scene> The all loop cover the active site (by migrate of 24 Å from unliganded PDE5 loop structure, so the active site become a closed pocket). [21]<br \>	+	* In case of Sildenafil binding, a turn and an 3ind10<scene name='60/604476/3-10helix/1'> helix (from 672 to 675)</scene> appear, and <scene name='60/604476/668_676/1'>from 668 to 676</scene> The all loop cover the active site (by migrate of 24 Å from unliganded PDE5 loop structure, so the active site become a closed pocket). <ref>[21]</ref><br \>
	* H-loop is less important in the interactions for Sildenafil and Icarisid II than cGMP.<br \>		* H-loop is less important in the interactions for Sildenafil and Icarisid II than cGMP.<br \>

	== Regulation ==		== Regulation ==
-	As it is written over, there are 2 regulatory domains (GAF A and GAF B). In cGMP pathway, PDE5 allows a negative feedback of the molecule: first, in presence of cGMP, it binds GAF A which stimulates the catalysis in the active site, and vice versa. Moreover, cGMP actives PKG which phophorylates PDE5, that is stimulated by the presence of cGMP on the GAF A or/and the active site. If the protein is not binding with cGMP but it is phophorylated, that stimulates the binding of cGMP on GAF A and the catalytic site. So cGMP presence overstimulates the catalysis [19]. And it also increase inhibitor's affinity[20] and without cGMP, inhibitor don’t bind the PDE5 [22].<br \>	+	As it is written over, there are 2 regulatory domains (GAF A and GAF B). In cGMP pathway, PDE5 allows a negative feedback of the molecule: first, in presence of cGMP, it binds GAF A which stimulates the catalysis in the active site, and vice versa. Moreover, cGMP actives PKG which phophorylates PDE5, that is stimulated by the presence of cGMP on the GAF A or/and the active site. If the protein is not binding with cGMP but it is phophorylated, that stimulates the binding of cGMP on GAF A and the catalytic site. So cGMP presence overstimulates the catalysis <ref>[19]</ref>. And it also increase inhibitor's affinity<ref>[20]</ref> and without cGMP, inhibitor don’t bind the PDE5 <ref>[22]</ref>.<br \>

	== The NO Pathway ==		== The NO Pathway ==
-	In the penile erection example, the nervous cell and/or epithelial cells are produced Nitrogen Oxide (NO) by the NOS (NO synthetase) from L-arginine and O2. They release NO in the extracellular environment going into vascular smooth cells and binding the Guanylyl Cyclase. This enzyme synthesizes cGMP from GMP, which stimulates the PKG. Finally, the calcium level is lower and the muscle cell relaxes and the Corpus Cavernosum rigidity increases. The PDE5 regulates the cGMP level making a negative feedback and can stop the rigidity. [22]<br \>	+	In the penile erection example, the nervous cell and/or epithelial cells are produced Nitrogen Oxide (NO) by the NOS (NO synthetase) from L-arginine and O2. They release NO in the extracellular environment going into vascular smooth cells and binding the Guanylyl Cyclase. This enzyme synthesizes cGMP from GMP, which stimulates the PKG. Finally, the calcium level is lower and the muscle cell relaxes and the Corpus Cavernosum rigidity increases. The PDE5 regulates the cGMP level making a negative feedback and can stop the rigidity. <ref>[22]</ref><br \>

	</StructureSection>		</StructureSection>
	== References ==		== References ==
	<references/>		<references/>