7wmt
From Proteopedia
(Difference between revisions)
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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. | |
<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 | + | 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> | ||
Current revision
Crystal structure of small molecule 13 bound to human Nicotinamide N-methyltransferase
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Categories: Homo sapiens | Large Structures | Inoue N | Kameda A | Kawagoe S | Kondo N | Tachibana Y | Takahashi Y | Uehara S | Yamada M | Yamamoto S | Yoshida S | Yoshimura N
