10mv: Difference between revisions

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'''Unreleased structure'''


The entry 10mv is ON HOLD  until Paper Publication
==N-Alkyl & N-Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors complex with Compound 15 ((3'R)-1'-(5-amino-1-phenyl-1H-pyrazole-4-carbonyl)-6-chloro-5-fluorospiro[[3,1]benzoxazine-4,3'-piperidin]-2(1H)-one)==
<StructureSection load='10mv' size='340' side='right'caption='[[10mv]], [[Resolution|resolution]] 1.66&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[10mv]] 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=10MV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=10MV 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]] 1.66&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1C6X:(4~{R})-1-(5-azanyl-1-phenyl-pyrazol-4-yl)carbonyl-6-chloranyl-5-fluoranyl-spiro[1~{H}-3,1-benzoxazine-4,3-piperidine]-2-one'>A1C6X</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=10mv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=10mv OCA], [https://pdbe.org/10mv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=10mv RCSB], [https://www.ebi.ac.uk/pdbsum/10mv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=10mv ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/KLKB1_HUMAN KLKB1_HUMAN] Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:[https://omim.org/entry/612423 612423]; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect.
== Function ==
[https://www.uniprot.org/uniprot/KLKB1_HUMAN KLKB1_HUMAN] The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Plasma kallikrein (pKal) is a trypsin-like serine protease involved in the kallikrein-kinin, renin-angiotensin, and complement pathways, making it an attractive target for diseases, such as hereditary angioedema, diabetic mellitus complications, and cerebrovascular disorders. As part of an internal program to develop orally bioavailable small-molecule pKal inhibitors, we report lead optimization efforts within the spirocarbamate scaffold, highlighting a structure-based drug design strategy to engineer hydrogen bond interactions with N-benzyl aminopyrazoles. Additionally, mitigation of time-dependent inhibition (TDI) liability and optimization of the overall profile were achieved through a two-pronged strategy: (1) incorporating increased Fsp(3) modifications via N-alkylation and (2) leveraging torsional strain in N-aryl analogs.


Authors:  
N‑Alkyl and N‑Aryl Aminopyrazole Spirocarbamates: A Two-Pronged Lead Optimization Strategy to Identify Orally Bioavailable Plasma Kallikrein Inhibitors.,Merchant RR, Chernyak N, Lopez JA, Sharp PP, Mandal M, He J, Hruza A, Rearden P, Tatosian DA, Esmay J, Yang S, Cheng AC, Ellsworth K, Ogawa A, Piou T, Fier P, Hicks J, Sinz C, Ogawa AK ACS Med Chem Lett. 2026 Feb 24;17(3):744-749. doi: , 10.1021/acsmedchemlett.6c00066. eCollection 2026 Mar 12. PMID:41847638<ref>PMID:41847638</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 10mv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cheng A]]
[[Category: Chernyak N]]
[[Category: Ellsworth K]]
[[Category: Esmay J]]
[[Category: Fier P]]
[[Category: He J]]
[[Category: Hicks J]]
[[Category: Hruza A]]
[[Category: Lin K]]
[[Category: Lopez JA]]
[[Category: Mandal M]]
[[Category: Merchant RR]]
[[Category: Ogawa A]]
[[Category: Piou T]]
[[Category: Rearden P]]
[[Category: Sharp PP]]
[[Category: Sinz C]]
[[Category: Tatosian DA]]
[[Category: Yang S]]
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