9td3: Difference between revisions

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~~'''Unreleased structure'''~~

~~The entry~~ 9td3 is ~~ON HOLD until sometime~~ in the future

==ERAP1 in complex with 1-[2-(6-bromo-2,2-difluoro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetamido]cyclohexane-1-carboxylic acid==

== Structural highlights ==

<table><tr><td colspan='2'>[[9td3]] 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=9TD3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9TD3 FirstGlance]. <br>

</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.57Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JVD:1-[2-[6-bromanyl-2,2-bis(fluoranyl)-3-oxidanylidene-1,4-benzoxazin-4-yl]ethanoylamino]cyclohexane-1-carboxylic+acid'>A1JVD</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=9td3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9td3 OCA], [https://pdbe.org/9td3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9td3 RCSB], [https://www.ebi.ac.uk/pdbsum/9td3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9td3 ProSAT]</span></td></tr>

</table>

== Function ==

[https://www.uniprot.org/uniprot/ERAP1_HUMAN ERAP1_HUMAN] Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney.<ref>PMID:15908954</ref> <ref>PMID:16286653</ref> <ref>PMID:21478864</ref>

== Publication Abstract from PubMed ==

Generative design and machine learning are increasingly prevalent in medicinal chemistry. To pilot the comprehensive use of automated molecular design on a project, the BRADSHAW platform was used to optimize a series of inhibitors of Endoplasmic Reticulum Aminopeptidase 1 (ERAP1), an emerging target in cancer immunotherapy and autoimmune diseases. Through four consecutive iterations applying in silico molecular generation, property prediction and filtering, we conducted a multiparameter optimization of potency, physicochemical properties and pharmacokinetics. Continuous refinement of Machine Learning (ML) models led to improved scoring accuracy and compound quality, culminating in identification of in vitro and in vivo tool molecules. We also discuss our reflections on the pilot and integration of automated design into medicinal chemistry projects, including observations of the human factors resulting from increased use of computational design, and recommendations for future projects.

~~Authors~~:

Automated Molecular Design in BRADSHAW, Applied to the Optimization of ERAP1 Inhibitors.,Law RP, Wall ID, Lonsdale R, Hryczanek RP, Barker D, Barrett TN, Bit RA, Coward JJ, Gray MW, Green DVS, Hall CJ, Hancock AP, Haslam C, Hirst DJ, Hryczanek HF, Hutchinson JP, Kitchen S, Marcus D, Marklew J, Mason J, Measom ND, Neu M, Peace S, Phillipou A, Pickett SD, Pogany P, Rowedder J, Rowland P, Scott-Stevens P, Seal GAL, Sheehan H, Stratikos E, Tayler C, Taylor JA, Tinworth CP, Vitulli G J Med Chem. 2026 Apr 13. doi: 10.1021/acs.jmedchem.5c03071. PMID:41973545<ref>PMID:41973545</ref>

~~Description~~:

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

[[Category: ~~Unreleased~~ Structures]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Rowland P]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9td3 is ON HOLD  until sometime in the future
+==ERAP1 in complex with 1-[2-(6-bromo-2,2-difluoro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetamido]cyclohexane-1-carboxylic acid==
+<StructureSection load='9td3' size='340' side='right'caption='[[9td3]], [[Resolution|resolution]] 1.57&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9td3]] 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=9TD3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9TD3 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.57&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JVD:1-[2-[6-bromanyl-2,2-bis(fluoranyl)-3-oxidanylidene-1,4-benzoxazin-4-yl]ethanoylamino]cyclohexane-1-carboxylic+acid'>A1JVD</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=9td3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9td3 OCA], [https://pdbe.org/9td3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9td3 RCSB], [https://www.ebi.ac.uk/pdbsum/9td3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9td3 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/ERAP1_HUMAN ERAP1_HUMAN] Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney.<ref>PMID:15908954</ref> <ref>PMID:16286653</ref> <ref>PMID:21478864</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Generative design and machine learning are increasingly prevalent in medicinal chemistry. To pilot the comprehensive use of automated molecular design on a project, the BRADSHAW platform was used to optimize a series of inhibitors of Endoplasmic Reticulum Aminopeptidase 1 (ERAP1), an emerging target in cancer immunotherapy and autoimmune diseases. Through four consecutive iterations applying in silico molecular generation, property prediction and filtering, we conducted a multiparameter optimization of potency, physicochemical properties and pharmacokinetics. Continuous refinement of Machine Learning (ML) models led to improved scoring accuracy and compound quality, culminating in identification of in vitro and in vivo tool molecules. We also discuss our reflections on the pilot and integration of automated design into medicinal chemistry projects, including observations of the human factors resulting from increased use of computational design, and recommendations for future projects.
-Authors:
+Automated Molecular Design in BRADSHAW, Applied to the Optimization of ERAP1 Inhibitors.,Law RP, Wall ID, Lonsdale R, Hryczanek RP, Barker D, Barrett TN, Bit RA, Coward JJ, Gray MW, Green DVS, Hall CJ, Hancock AP, Haslam C, Hirst DJ, Hryczanek HF, Hutchinson JP, Kitchen S, Marcus D, Marklew J, Mason J, Measom ND, Neu M, Peace S, Phillipou A, Pickett SD, Pogany P, Rowedder J, Rowland P, Scott-Stevens P, Seal GAL, Sheehan H, Stratikos E, Tayler C, Taylor JA, Tinworth CP, Vitulli G J Med Chem. 2026 Apr 13. doi: 10.1021/acs.jmedchem.5c03071. PMID:41973545<ref>PMID:41973545</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9td3" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Rowland P]]