7wmt - Revision history

OCA at 19:44, 29 May 2024

2024-05-29T19:44:33Z

←Older revision		Revision as of 19:44, 29 May 2024
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7wmt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WMT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WMT FirstGlance]. <br>		<table><tr><td colspan='2'>[[7wmt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WMT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WMT FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1IV:[(2~{R},4~{S})-4-[2-(aminomethyl)imidazol-1-yl]-2-[1-[(4-chlorophenyl)methyl]-5-methyl-indol-2-yl]pyrrolidin-1-yl]-(1~{H}-pyrrolo[2,3-b]pyridin-5-yl)methanone'>1IV</scene></td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.77Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1IV:[(2~{R},4~{S})-4-[2-(aminomethyl)imidazol-1-yl]-2-[1-[(4-chlorophenyl)methyl]-5-methyl-indol-2-yl]pyrrolidin-1-yl]-(1~{H}-pyrrolo[2,3-b]pyridin-5-yl)methanone'>1IV</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7wmt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wmt OCA], [https://pdbe.org/7wmt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wmt RCSB], [https://www.ebi.ac.uk/pdbsum/7wmt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wmt ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7wmt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wmt OCA], [https://pdbe.org/7wmt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wmt RCSB], [https://www.ebi.ac.uk/pdbsum/7wmt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wmt ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/NNMT_HUMAN NNMT_HUMAN]] Catalyzes the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for biotransformation of many drugs and xenobiotic compounds.	+	[https://www.uniprot.org/uniprot/NNMT_HUMAN NNMT_HUMAN] Catalyzes the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for biotransformation of many drugs and xenobiotic compounds.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
-	Recent technological innovations have led to the development of methods for the rapid identification of high-affinity macrocyclic peptides for a wide range of targets; however, it is still challenging to achieve the desired activity and membrane permeability at the same time. Here, we propose a novel small molecule lead discovery strategy, ''Peptide-to-Small Molecule'', which is a combination of rapid identification of high-affinity macrocyclic peptides via peptide display screening followed by pharmacophore-guided de novo design of small molecules, and demonstrate the applicability using nicotinamide N-methyltransferase (NNMT) as a target. Affinity selection by peptide display technology identified macrocyclic peptide 1 that exhibited good enzymatic inhibitory activity but no cell-based activity. Thereafter, a peptide pharmacophore-guided de novo design and further structure-based optimization resulted in highly potent and cell-active small molecule 14 (cell-free ~~IC50~~ = 0.0011 muM, cell-based ~~IC50~~ = 0.40 muM), indicating that this strategy could be a new option for drug discovery.	+	Recent technological innovations have led to the development of methods for the rapid identification of high-affinity macrocyclic peptides for a wide range of targets; however, it is still challenging to achieve the desired activity and membrane permeability at the same time. Here, we propose a novel small molecule lead discovery strategy, ''Peptide-to-Small Molecule'', which is a combination of rapid identification of high-affinity macrocyclic peptides via peptide display screening followed by pharmacophore-guided de novo design of small molecules, and demonstrate the applicability using nicotinamide N-methyltransferase (NNMT) as a target. Affinity selection by peptide display technology identified macrocyclic peptide 1 that exhibited good enzymatic inhibitory activity but no cell-based activity. Thereafter, a peptide pharmacophore-guided de novo design and further structure-based optimization resulted in highly potent and cell-active small molecule 14 (cell-free IC(50) = 0.0011 muM, cell-based IC(50) = 0.40 muM), indicating that this strategy could be a new option for drug discovery.

-	Peptide-to-Small Molecule: A Pharmacophore-Guided Small Molecule Lead Generation Strategy from High-Affinity Macrocyclic Peptides.,Yoshida S, Uehara S, Kondo N, Takahashi Y, Yamamoto S, Kameda A, Kawagoe S, Inoue N, Yamada M, Yoshimura N, Tachibana Y J Med Chem. 2022 Aug 11;65(15):10655-10673. doi: 10.1021/acs.jmedchem.2c00919., Epub 2022 Jul 29. PMID:35904556<ref>PMID:35904556</ref>	+	Peptide-to-Small Molecule: A Pharmacophore-Guided Small Molecule Lead Generation Strategy from High-Affinity Macrocyclic Peptides.,Yoshida S, Uehara S, Kondo N, Takahashi Y, Yamamoto S, Kameda A, Kawagoe S, Inoue N, Yamada M, Yoshimura N, Tachibana Y J Med Chem. 2022 Aug 11;65(15):10655-10673. doi: 10.1021/acs.jmedchem.2c00919. , Epub 2022 Jul 29. PMID:35904556<ref>PMID:35904556</ref>

	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

OCA at 19:31, 7 September 2022

2022-09-07T19:31:29Z

←Older revision		Revision as of 19:31, 7 September 2022
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	==Crystal structure of small molecule 13 bound to human Nicotinamide N-methyltransferase==		==Crystal structure of small molecule 13 bound to human Nicotinamide N-methyltransferase==
-	<StructureSection load='7wmt' size='340' side='right'caption='[[7wmt]]' scene=''>	+	<StructureSection load='7wmt' size='340' side='right'caption='[[7wmt]], [[Resolution\|resolution]] 1.77Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WMT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WMT FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7wmt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WMT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WMT FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7wmt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wmt OCA], [https://pdbe.org/7wmt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wmt RCSB], [https://www.ebi.ac.uk/pdbsum/7wmt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wmt ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1IV:[(2~{R},4~{S})-4-[2-(aminomethyl)imidazol-1-yl]-2-[1-[(4-chlorophenyl)methyl]-5-methyl-indol-2-yl]pyrrolidin-1-yl]-(1~{H}-pyrrolo[2,3-b]pyridin-5-yl)methanone'>1IV</scene></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7wmt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wmt OCA], [https://pdbe.org/7wmt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wmt RCSB], [https://www.ebi.ac.uk/pdbsum/7wmt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wmt ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/NNMT_HUMAN NNMT_HUMAN]] Catalyzes the N-methylation of nicotinamide and other pyridines to form pyridinium ions. This activity is important for biotransformation of many drugs and xenobiotic compounds.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Recent technological innovations have led to the development of methods for the rapid identification of high-affinity macrocyclic peptides for a wide range of targets; however, it is still challenging to achieve the desired activity and membrane permeability at the same time. Here, we propose a novel small molecule lead discovery strategy, ''Peptide-to-Small Molecule'', which is a combination of rapid identification of high-affinity macrocyclic peptides via peptide display screening followed by pharmacophore-guided de novo design of small molecules, and demonstrate the applicability using nicotinamide N-methyltransferase (NNMT) as a target. Affinity selection by peptide display technology identified macrocyclic peptide 1 that exhibited good enzymatic inhibitory activity but no cell-based activity. Thereafter, a peptide pharmacophore-guided de novo design and further structure-based optimization resulted in highly potent and cell-active small molecule 14 (cell-free IC50 = 0.0011 muM, cell-based IC50 = 0.40 muM), indicating that this strategy could be a new option for drug discovery.
		+
		+	Peptide-to-Small Molecule: A Pharmacophore-Guided Small Molecule Lead Generation Strategy from High-Affinity Macrocyclic Peptides.,Yoshida S, Uehara S, Kondo N, Takahashi Y, Yamamoto S, Kameda A, Kawagoe S, Inoue N, Yamada M, Yoshimura N, Tachibana Y J Med Chem. 2022 Aug 11;65(15):10655-10673. doi: 10.1021/acs.jmedchem.2c00919., Epub 2022 Jul 29. PMID:35904556<ref>PMID:35904556</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7wmt" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Inoue N]]		[[Category: Inoue N]]

OCA at 06:38, 31 August 2022

2022-08-31T06:38:14Z

←Older revision		Revision as of 06:38, 31 August 2022
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-	'''Unreleased structure'''

-	~~The entry~~ 7wmt ~~is ON HOLD until Paper Publication~~	+	==Crystal structure of small molecule 13 bound to human Nicotinamide N-methyltransferase==
-		+	<StructureSection load='7wmt' size='340' side='right'caption='[[7wmt]]' scene=''>
-	~~Authors~~: ~~Yoshida, S~~.~~, Uehara, S~~.~~, Kondo, N~~.~~, Takahashi, Y~~.~~, Yamamoto, S~~.~~, Kameda, A~~., ~~Kawagoe, S~~., ~~Inoue, N~~., ~~Yamada, M~~., ~~Yoshimura, N~~., ~~Tachibana, Y~~.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WMT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WMT FirstGlance]. <br>
-	~~Description: Crystal structure of small molecule 13 bound to human Nicotinamide N-methyltransferase~~	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7wmt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wmt OCA], [https://pdbe.org/7wmt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wmt RCSB], [https://www.ebi.ac.uk/pdbsum/7wmt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wmt ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Kondo,~~ N]]	+	__TOC__
-	[[Category: ~~Yoshimura, N~~]]	+	</StructureSection>
-	[[Category: ~~Yamamoto,~~ S]]	+	[[Category: Large Structures]]
-	[[Category: ~~Uehara, S~~]]	+	[[Category: Inoue N]]
-	[[Category: ~~Takahashi,~~ Y]]	+	[[Category: Kameda A]]
-	[[Category: ~~Yoshida, S~~]]	+	[[Category: Kawagoe S]]
-	[[Category: ~~Inoue, N~~]]	+	[[Category: Kondo N]]
-	[[Category: ~~Tachibana, Y~~]]	+	[[Category: Tachibana Y]]
-	[[Category: ~~Kameda, A~~]]	+	[[Category: Takahashi Y]]
-	[[Category: ~~Yamada, M~~]]	+	[[Category: Uehara S]]
-	[[Category: ~~Kawagoe, S~~]]	+	[[Category: Yamada M]]
		+	[[Category: Yamamoto S]]
		+	[[Category: Yoshida S]]
		+	[[Category: Yoshimura N]]

OCA at 05:46, 2 February 2022

2022-02-02T05:46:50Z

←Older revision		Revision as of 05:46, 2 February 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7wmt is ON HOLD	+	The entry 7wmt is ON HOLD until Paper Publication

	Authors: Yoshida, S., Uehara, S., Kondo, N., Takahashi, Y., Yamamoto, S., Kameda, A., Kawagoe, S., Inoue, N., Yamada, M., Yoshimura, N., Tachibana, Y.		Authors: Yoshida, S., Uehara, S., Kondo, N., Takahashi, Y., Yamamoto, S., Kameda, A., Kawagoe, S., Inoue, N., Yamada, M., Yoshimura, N., Tachibana, Y.

OCA: Protected "7wmt" [edit=sysop:move=sysop]

2022-01-27T05:45:20Z

Protected "7wmt" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:45, 27 January 2022

OCA: New page: '''Unreleased structure''' The entry 7wmt is ON HOLD Authors: Yoshida, S., Uehara, S., Kondo, N., Takahashi, Y., Yamamoto, S., Kameda, A., Kawagoe, S., Inoue, N., Yamada, M., Yoshimura,...

2022-01-27T05:45:19Z

New page: '''Unreleased structure''' The entry 7wmt is ON HOLD Authors: Yoshida, S., Uehara, S., Kondo, N., Takahashi, Y., Yamamoto, S., Kameda, A., Kawagoe, S., Inoue, N., Yamada, M., Yoshimura,...

New page

'''Unreleased structure'''

The entry 7wmt is ON HOLD

Authors: Yoshida, S., Uehara, S., Kondo, N., Takahashi, Y., Yamamoto, S., Kameda, A., Kawagoe, S., Inoue, N., Yamada, M., Yoshimura, N., Tachibana, Y.

Description: Crystal structure of small molecule 13 bound to human Nicotinamide N-methyltransferase
[[Category: Unreleased Structures]]
[[Category: Kondo, N]]
[[Category: Yoshimura, N]]
[[Category: Yamamoto, S]]
[[Category: Uehara, S]]
[[Category: Takahashi, Y]]
[[Category: Yoshida, S]]
[[Category: Inoue, N]]
[[Category: Tachibana, Y]]
[[Category: Kameda, A]]
[[Category: Yamada, M]]
[[Category: Kawagoe, S]]