3ufl: Difference between revisions

Latest revision as of 09:45, 30 October 2024

Discovery of Pyrrolidine-based b-Secretase Inhibitors: Lead Advancement through Conformational Design for Maintenance of Ligand Binding Efficiency

Structural highlights

3ufl is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:	508, GOL, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BACE1_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.^[1] ^[2]

Publication Abstract from PubMed

We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.

Discovery of pyrrolidine-based beta-secretase inhibitors: Lead advancement through conformational design for maintenance of ligand binding efficiency.,Stachel SJ, Steele TG, Petrocchi A, Haugabook SJ, McGaughey G, Katharine Holloway M, Allison T, Munshi S, Zuck P, Colussi D, Tugasheva K, Wolfe A, Graham SL, Vacca JP Bioorg Med Chem Lett. 2012 Jan 1;22(1):240-4. Epub 2011 Nov 12. PMID:22130130^[3]

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

References

↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
↑ Stachel SJ, Steele TG, Petrocchi A, Haugabook SJ, McGaughey G, Katharine Holloway M, Allison T, Munshi S, Zuck P, Colussi D, Tugasheva K, Wolfe A, Graham SL, Vacca JP. Discovery of pyrrolidine-based beta-secretase inhibitors: Lead advancement through conformational design for maintenance of ligand binding efficiency. Bioorg Med Chem Lett. 2012 Jan 1;22(1):240-4. Epub 2011 Nov 12. PMID:22130130 doi:10.1016/j.bmcl.2011.11.024

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OCA

[1] Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483

[2] Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357

[3] Stachel SJ, Steele TG, Petrocchi A, Haugabook SJ, McGaughey G, Katharine Holloway M, Allison T, Munshi S, Zuck P, Colussi D, Tugasheva K, Wolfe A, Graham SL, Vacca JP. Discovery of pyrrolidine-based beta-secretase inhibitors: Lead advancement through conformational design for maintenance of ligand binding efficiency. Bioorg Med Chem Lett. 2012 Jan 1;22(1):240-4. Epub 2011 Nov 12. PMID:22130130 doi:10.1016/j.bmcl.2011.11.024

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='3ufl' size='340' side='right'caption='[[3ufl]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3ufl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UFL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UFL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3ufl]] 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=3UFL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UFL FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=508:(1R,4S)-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,3-PYRROLIDIN]-4-YL[(2S,4R)-2,4-DIPHENYLPIPERIDIN-1-YL]METHANONE'>508</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.9&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=508:(1R,4S)-3,4-DIHYDRO-2H-SPIRO[NAPHTHALENE-1,3-PYRROLIDIN]-4-YL[(2S,4R)-2,4-DIPHENYLPIPERIDIN-1-YL]METHANONE'>508</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </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=3ufl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ufl OCA], [https://pdbe.org/3ufl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ufl RCSB], [https://www.ebi.ac.uk/pdbsum/3ufl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ufl ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
+[https://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Memapsin 2]]
+[[Category: Allison T]]
-[[Category: Allison, T]]
+[[Category: Munshi S]]
-[[Category: Munshi, S]]
+[[Category: Soisson SM]]
-[[Category: Soisson, S M]]
-[[Category: Aspartyl protease]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]

3ufl: Difference between revisions

Latest revision as of 09:45, 30 October 2024

Discovery of Pyrrolidine-based b-Secretase Inhibitors: Lead Advancement through Conformational Design for Maintenance of Ligand Binding Efficiency

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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