2h7n - Revision history

OCA: Redirecting to 4u0k

2014-07-30T07:29:27Z

Redirecting to 4u0k

←Older revision		Revision as of 07:29, 30 July 2014
Line 1:		Line 1:
-	[[~~Image:2h7n.png\|left\|200px~~]]	+	#REDIRECT [[4u0k]] This PDB entry is obsolete and replaced by 4u0k
-		+
-	~~{{STRUCTURE_2h7n\|~~ PDB~~=2h7n \| SCENE= }}~~	+
-		+
-	~~===Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide===~~	+
-		+
-	~~{{ABSTRACT_PUBMED_17034137}}~~	+
-		+
-	~~==About this Structure==~~	+
-	~~[[2h7n]]~~ is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7N OCA].	+
-		+
-	~~==See Also==~~	+
-	*[[Enoyl-Acyl-Carrier Protein Reductase\|Enoyl-Acyl-Carrier Protein Reductase]]	+
-		+
-	~~==Reference==~~	+
-	~~<ref group="xtra">PMID:017034137</ref><references group="xtra"/>~~	+
-	~~[[Category: Mycobacterium tuberculosis]]~~	+
-	~~[[Category: Alian, A.]]~~	+
-	~~[[Category: He, X.]]~~	+
-	~~[[Category: Montellano, P R.Ortiz de.]]~~	+
-	~~[[Category: Stroud, R.]]~~	+
-	~~[[Category: Enoyl acyl carrier reductase]]~~	+
-	~~[[Category: Inha]]~~	+
-	~~[[Category: Oxidoreductase]]~~	+
-	~~[[Category: Pyrrolidine carboxamide]]~~	+

OCA at 09:03, 20 October 2012

2012-10-20T09:03:38Z

←Older revision		Revision as of 09:03, 20 October 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[2h7n]] is a 1 chain structure ~~of [[Enoyl-Acyl-Carrier Protein Reductase]]~~ with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7N OCA].	+	[[2h7n]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7N OCA].

	==See Also==		==See Also==

OCA: Protected "2h7n" [edit=sysop:move=sysop]

2012-07-25T21:39:01Z

Protected "2h7n" [edit=sysop:move=sysop]

←Older revision

Revision as of 21:39, 25 July 2012

OCA at 21:39, 25 July 2012

2012-07-25T21:39:00Z

←Older revision		Revision as of 21:39, 25 July 2012
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-	{{Seed}}
	[[Image:2h7n.png\|left\|200px]]		[[Image:2h7n.png\|left\|200px]]

-	<!--
-	The line below this paragraph, containing "STRUCTURE_2h7n", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	or leave the SCENE parameter empty for the default display.
-	-->
	{{STRUCTURE_2h7n\| PDB=2h7n \| SCENE= }}		{{STRUCTURE_2h7n\| PDB=2h7n \| SCENE= }}

	===Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide===		===Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide===

-
-	<!--
-	The line below this paragraph, {{ABSTRACT_PUBMED_17034137}}, adds the Publication Abstract to the page
-	(as it appears on PubMed at http://www.pubmed.gov), where 17034137 is the PubMed ID number.
-	-->
	{{ABSTRACT_PUBMED_17034137}}		{{ABSTRACT_PUBMED_17034137}}

	==About this Structure==		==About this Structure==
-	~~2H7N~~ is a 1 chain structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7N OCA].	+	[[2h7n]] is a 1 chain structure of [[Enoyl-Acyl-Carrier Protein Reductase]] with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7N OCA].
		+
		+	==See Also==
		+	*[[Enoyl-Acyl-Carrier Protein Reductase\|Enoyl-Acyl-Carrier Protein Reductase]]

	==Reference==		==Reference==
-	<ref group="xtra">PMID:~~17034137~~</ref><references group="xtra"/>	+	<ref group="xtra">PMID:017034137</ref><references group="xtra"/>
	[[Category: Mycobacterium tuberculosis]]		[[Category: Mycobacterium tuberculosis]]
	[[Category: Alian, A.]]		[[Category: Alian, A.]]
Line 33:		Line 24:
	[[Category: Oxidoreductase]]		[[Category: Oxidoreductase]]
	[[Category: Pyrrolidine carboxamide]]		[[Category: Pyrrolidine carboxamide]]
-
-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Feb 16 19:08:10 2009''

OCA at 17:08, 16 February 2009

2009-02-16T17:08:13Z

←Older revision		Revision as of 17:08, 16 February 2009
Line 20:		Line 20:

	==About this Structure==		==About this Structure==
-	2H7N is a ~~[[Single protein]]~~ structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7N OCA].	+	2H7N is a 1 chain structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7N OCA].

	==Reference==		==Reference==
-	Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis., He X, Alian A, Stroud R, Ortiz de Montellano PR, J Med Chem. 2006 Oct 19;49(21):6308-23. PMID:~~[http:~~//~~www.ncbi.nlm.nih.gov/pubmed/17034137 17034137]~~	+	<ref group="xtra">PMID:17034137</ref><references group="xtra"/>
	[[Category: Mycobacterium tuberculosis]]		[[Category: Mycobacterium tuberculosis]]
-	[[Category: Single protein]]
	[[Category: Alian, A.]]		[[Category: Alian, A.]]
	[[Category: He, X.]]		[[Category: He, X.]]
Line 35:		Line 34:
	[[Category: Pyrrolidine carboxamide]]		[[Category: Pyrrolidine carboxamide]]

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on ~~Sun Jul 27 23~~:29:~~32 2008~~''	+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Feb 16 19:08:10 2009''

OCA at 20:29, 27 July 2008

2008-07-27T20:29:38Z

←Older revision		Revision as of 20:29, 27 July 2008
Line 1:		Line 1:
-	[[Image:2h7n.~~jpg~~\|left\|200px]]	+	{{Seed}}
		+	[[Image:2h7n.png\|left\|200px]]

	<!--		<!--
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	{{STRUCTURE_2h7n\| PDB=2h7n \| SCENE= }}		{{STRUCTURE_2h7n\| PDB=2h7n \| SCENE= }}

-	~~'''~~Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide~~'''~~	+	===Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide===


-	~~==Overview==~~	+	<!--
-	~~In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis~~, ~~there is an urgent need to discover antituberculosis agent with novel structures. InhA~~, the ~~enoyl acyl carrier protein reductase~~ (~~ENR~~) ~~from M. tuberculosis~~, is ~~one of~~ the ~~key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective antimicrobial target~~. ~~We report here the discovery, through high~~-throughput screening, of a series of pyrrolidine carboxamides as a novel class of potent InhA inhibitors. Crystal structures of InhA complexed with three inhibitors have been used to elucidate the inhibitor binding mode. The potency of the lead compound was improved over 160-fold by subsequent optimization through iterative microtiter library synthesis followed by in situ activity screening without purification. Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA.	+	The line below this paragraph, {{ABSTRACT_PUBMED_17034137}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 17034137 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_17034137}}

	==About this Structure==		==About this Structure==
Line 30:		Line 34:
	[[Category: Oxidoreductase]]		[[Category: Oxidoreductase]]
	[[Category: Pyrrolidine carboxamide]]		[[Category: Pyrrolidine carboxamide]]
-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun ~~May 4 05~~:57:59 2008''	+
		+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 23:29:32 2008''

OCA at 02:58, 4 May 2008

2008-05-04T02:58:02Z

←Older revision		Revision as of 02:58, 4 May 2008
Line 1:		Line 1:
	[[Image:2h7n.jpg\|left\|200px]]		[[Image:2h7n.jpg\|left\|200px]]

-	~~{{Structure~~	+	<!--
-	~~\|PDB= 2h7n \|SIZE=350\|CAPTION= <scene name='initialview01'>2h7n</scene>~~, ~~resolution 1~~.~~9Å~~	+	The line below this paragraph, containing "STRUCTURE_2h7n", creates the "Structure Box" on the page.
-	~~\|SITE=~~	+	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	~~\|LIGAND= <scene name='pdbligand=744:~~(3S)~~-N-~~(~~5-CHLORO-2-METHYLPHENYL~~)~~-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDE'>744</scene>~~, ~~<scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>~~	+	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	~~\|ACTIVITY= <span class='plainlinks'>[http://en~~.~~wikipedia.org/wiki/Enoyl~~-~~[acyl~~-~~carrier-protein]_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.9 1.3.1.9] </span~~>	+	or leave the SCENE parameter empty for the default display.
-	\|~~GENE~~= ~~inhA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis])~~	+	-->
-	\|~~DOMAIN~~=	+	{{STRUCTURE_2h7n\| PDB=2h7n \| SCENE= }}
-	~~\|RELATEDENTRY=[[1eny\|1ENY]], [[1p45\|1P45]], [[1enz\|1ENZ]], [[2b35\|2B35]], [[2b36\|2B36]], [[1bvr\|1BVR]]~~	+
-	\|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2h7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h7n OCA], [http://www.ebi.ac.uk/pdbsum/2h7n PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2h7n RCSB]</span>	+
-	}}	+

	'''Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide'''		'''Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide'''
Line 23:		Line 20:
	==Reference==		==Reference==
	Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis., He X, Alian A, Stroud R, Ortiz de Montellano PR, J Med Chem. 2006 Oct 19;49(21):6308-23. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17034137 17034137]		Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis., He X, Alian A, Stroud R, Ortiz de Montellano PR, J Med Chem. 2006 Oct 19;49(21):6308-23. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17034137 17034137]
-	[[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]
	[[Category: Mycobacterium tuberculosis]]		[[Category: Mycobacterium tuberculosis]]
	[[Category: Single protein]]		[[Category: Single protein]]
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	[[Category: Montellano, P R.Ortiz de.]]		[[Category: Montellano, P R.Ortiz de.]]
	[[Category: Stroud, R.]]		[[Category: Stroud, R.]]
-	[[Category: ~~enoyl~~ acyl carrier reductase]]	+	[[Category: Enoyl acyl carrier reductase]]
-	[[Category: ~~inha~~]]	+	[[Category: Inha]]
-	[[Category: ~~oxidoreductase~~]]	+	[[Category: Oxidoreductase]]
-	[[Category: ~~pyrrolidine~~ carboxamide]]	+	[[Category: Pyrrolidine carboxamide]]
-		+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 05:57:59 2008''
-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on ~~Mon Mar 31 03~~:26:38 2008''	+

OCA at 00:26, 31 March 2008

2008-03-31T00:26:38Z

←Older revision		Revision as of 00:26, 31 March 2008
Line 4:		Line 4:
	\|PDB= 2h7n \|SIZE=350\|CAPTION= <scene name='initialview01'>2h7n</scene>, resolution 1.9Å		\|PDB= 2h7n \|SIZE=350\|CAPTION= <scene name='initialview01'>2h7n</scene>, resolution 1.9Å
	\|SITE=		\|SITE=
-	\|LIGAND= ~~<scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene> and~~ <scene name='pdbligand=744:(3S)-N-(5-CHLORO-2-METHYLPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDE'>744</scene>	+	\|LIGAND= <scene name='pdbligand=744:(3S)-N-(5-CHLORO-2-METHYLPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDE'>744</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>
-	\|ACTIVITY= [http://en.wikipedia.org/wiki/Enoyl-[acyl-carrier-protein]_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.9 1.3.1.9]	+	\|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Enoyl-[acyl-carrier-protein]_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.9 1.3.1.9] </span>
	\|GENE= inhA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis])		\|GENE= inhA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis])
		+	\|DOMAIN=
		+	\|RELATEDENTRY=[[1eny\|1ENY]], [[1p45\|1P45]], [[1enz\|1ENZ]], [[2b35\|2B35]], [[2b36\|2B36]], [[1bvr\|1BVR]]
		+	\|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2h7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h7n OCA], [http://www.ebi.ac.uk/pdbsum/2h7n PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2h7n RCSB]</span>
	}}		}}

Line 27:		Line 30:
	[[Category: Montellano, P R.Ortiz de.]]		[[Category: Montellano, P R.Ortiz de.]]
	[[Category: Stroud, R.]]		[[Category: Stroud, R.]]
-	[[Category: 744]]
-	[[Category: NAD]]
	[[Category: enoyl acyl carrier reductase]]		[[Category: enoyl acyl carrier reductase]]
	[[Category: inha]]		[[Category: inha]]
Line 34:		Line 35:
	[[Category: pyrrolidine carboxamide]]		[[Category: pyrrolidine carboxamide]]

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on ~~Thu~~ Mar ~~20 17~~:13:41 2008''	+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:26:38 2008''

OCA at 15:13, 20 March 2008

2008-03-20T15:13:44Z

←Older revision		Revision as of 15:13, 20 March 2008
Line 1:		Line 1:
-	[[Image:2h7n.jpg\|left\|200px]]~~<br /><applet load~~="2h7n~~" size~~="350~~" color~~=~~"white" frame~~=~~"true" align="right" spinBox="true"~~	+	[[Image:2h7n.jpg\|left\|200px]]
-	~~caption="~~2h7n, resolution 1.9Å" />	+
-	'''Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide'''~~<br />~~	+	{{Structure
		+	\|PDB= 2h7n \|SIZE=350\|CAPTION= <scene name='initialview01'>2h7n</scene>, resolution 1.9Å
		+	\|SITE=
		+	\|LIGAND= <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene> and <scene name='pdbligand=744:(3S)-N-(5-CHLORO-2-METHYLPHENYL)-1-CYCLOHEXYL-5-OXOPYRROLIDINE-3-CARBOXAMIDE'>744</scene>
		+	\|ACTIVITY= [http://en.wikipedia.org/wiki/Enoyl-[acyl-carrier-protein]_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.9 1.3.1.9]
		+	\|GENE= inhA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis])
		+	}}
		+
		+	'''Crystal structure of Mycobacterium tuberculosis enoyl reductase (InhA) complexed with N-(5-chloro-2-methylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide'''
		+

	==Overview==		==Overview==
Line 7:		Line 16:

	==About this Structure==		==About this Structure==
-	2H7N is a [~~http://en.wikipedia.org/wiki/Single_protein~~ Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] ~~with <scene name='pdbligand=NAD:'>NAD</scene> and <scene name='pdbligand=744:'>744</scene> as [http://en~~.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Enoyl-[acyl-carrier-protein]_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.9 1.3.1.9] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7N OCA].	+	2H7N is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H7N OCA].

	==Reference==		==Reference==
-	Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis., He X, Alian A, Stroud R, Ortiz de Montellano PR, J Med Chem. 2006 Oct 19;49(21):6308-23. PMID:[http://~~ispc~~.~~weizmann~~.ac.~~il/~~/~~pmbin~~/~~getpm?pmid=~~17034137 17034137]	+	Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis., He X, Alian A, Stroud R, Ortiz de Montellano PR, J Med Chem. 2006 Oct 19;49(21):6308-23. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17034137 17034137]
	[[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]		[[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]
	[[Category: Mycobacterium tuberculosis]]		[[Category: Mycobacterium tuberculosis]]
Line 25:		Line 34:
	[[Category: pyrrolidine carboxamide]]		[[Category: pyrrolidine carboxamide]]

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu ~~Feb 21~~ 17:39:02 2008''	+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:13:41 2008''

OCA at 15:39, 21 February 2008

2008-02-21T15:39:05Z

←Older revision		Revision as of 15:39, 21 February 2008
Line 4:		Line 4:

	==Overview==		==Overview==
-	In view of the worldwide spread of multidrug resistance of Mycobacterium, tuberculosis, there is an urgent need to discover antituberculosis agent, with novel structures. InhA, the enoyl acyl carrier protein reductase, (ENR) from M. tuberculosis, is one of the key enzymes involved in the, mycobacterial fatty acid elongation cycle and has been validated as an, effective antimicrobial target. We report here the discovery, through, high-throughput screening, of a series of pyrrolidine carboxamides as a, novel class of potent InhA inhibitors. Crystal structures of InhA, complexed with three inhibitors have been used to elucidate the inhibitor, binding mode. The potency of the lead compound was improved over 160-fold, by subsequent optimization through iterative microtiter library synthesis, followed by in situ activity screening without purification. Resolution of, racemic mixtures of several inhibitors indicate that only one enantiomer, is active as an inhibitor of InhA.	+	In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antituberculosis agent with novel structures. InhA, the enoyl acyl carrier protein reductase (ENR) from M. tuberculosis, is one of the key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective antimicrobial target. We report here the discovery, through high-throughput screening, of a series of pyrrolidine carboxamides as a novel class of potent InhA inhibitors. Crystal structures of InhA complexed with three inhibitors have been used to elucidate the inhibitor binding mode. The potency of the lead compound was improved over 160-fold by subsequent optimization through iterative microtiter library synthesis followed by in situ activity screening without purification. Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA.

	==About this Structure==		==About this Structure==
Line 16:		Line 16:
	[[Category: Alian, A.]]		[[Category: Alian, A.]]
	[[Category: He, X.]]		[[Category: He, X.]]
-	[[Category: Montellano, P.R.Ortiz.de.]]	+	[[Category: Montellano, P R.Ortiz de.]]
	[[Category: Stroud, R.]]		[[Category: Stroud, R.]]
	[[Category: 744]]		[[Category: 744]]
Line 25:		Line 25:
	[[Category: pyrrolidine carboxamide]]		[[Category: pyrrolidine carboxamide]]

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on ~~Tue Jan 29 20~~:15:59 2008''	+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:39:02 2008''