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[[ | ==Exploitation of hydrogen bonding constraints and flat hydrophobic energy landscapes in Pim-1 kinase needle screening and inhibitor design== | ||
<StructureSection load='3vbw' size='340' side='right' caption='[[3vbw]], [[Resolution|resolution]] 2.48Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3vbw]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VBW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3VBW FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0FN:1,3-DIOXO-2,3-DIHYDRO-1H-INDENE-2-CARBONITRILE'>0FN</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3vbq|3vbq]], [[3vbt|3vbt]], [[3vbv|3vbv]], [[3vbx|3vbx]], [[3vby|3vby]], [[3vc4|3vc4]]</td></tr> | |||
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3vbw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vbw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3vbw RCSB], [http://www.ebi.ac.uk/pdbsum/3vbw PDBsum]</span></td></tr> | |||
<table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We have studied the subtleties of fragment docking and binding using data generated in a Pim-1 kinase inhibitor program. Crystallographic and docking data analyses have been undertaken using inhibitor complexes derived from an in-house surface plasmon resonance (SPR) fragment screen, a virtual needle screen, and a de novo designed fragment inhibitor hybrid. These investigations highlight that fragments that do not fill their binding pocket can exhibit promiscuous hydrophobic interactions due to the lack of steric constraints imposed on them by the boundaries of said pocket. As a result, docking modes that disagree with an observed crystal structure but maintain key crystallographically observed hydrogen bonds still have potential value in ligand design and optimization. This observation runs counter to the lore in fragment-based drug design that all fragment elaboration must be based on the parent crystal structure alone. | |||
Implications of Promiscuous Pim-1 Kinase Fragment Inhibitor Hydrophobic Interactions for Fragment-Based Drug Design.,Good AC, Liu J, Hirth B, Asmussen G, Xiang Y, Biemann HP, Bishop KA, Fremgen T, Fitzgerald M, Gladysheva T, Jain A, Jancsics K, Metz M, Papoulis A, Skerlj R, Stepp JD, Wei RR J Med Chem. 2012 Mar 5. PMID:22339127<ref>PMID:22339127</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
*[[Proto-oncogene serine/threonine-protein kinase|Proto-oncogene serine/threonine-protein kinase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
[[ | |||
== | |||
< | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Non-specific serine/threonine protein kinase]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
Revision as of 11:34, 5 June 2014
Exploitation of hydrogen bonding constraints and flat hydrophobic energy landscapes in Pim-1 kinase needle screening and inhibitor designExploitation of hydrogen bonding constraints and flat hydrophobic energy landscapes in Pim-1 kinase needle screening and inhibitor design
Structural highlights
Publication Abstract from PubMedWe have studied the subtleties of fragment docking and binding using data generated in a Pim-1 kinase inhibitor program. Crystallographic and docking data analyses have been undertaken using inhibitor complexes derived from an in-house surface plasmon resonance (SPR) fragment screen, a virtual needle screen, and a de novo designed fragment inhibitor hybrid. These investigations highlight that fragments that do not fill their binding pocket can exhibit promiscuous hydrophobic interactions due to the lack of steric constraints imposed on them by the boundaries of said pocket. As a result, docking modes that disagree with an observed crystal structure but maintain key crystallographically observed hydrogen bonds still have potential value in ligand design and optimization. This observation runs counter to the lore in fragment-based drug design that all fragment elaboration must be based on the parent crystal structure alone. Implications of Promiscuous Pim-1 Kinase Fragment Inhibitor Hydrophobic Interactions for Fragment-Based Drug Design.,Good AC, Liu J, Hirth B, Asmussen G, Xiang Y, Biemann HP, Bishop KA, Fremgen T, Fitzgerald M, Gladysheva T, Jain A, Jancsics K, Metz M, Papoulis A, Skerlj R, Stepp JD, Wei RR J Med Chem. 2012 Mar 5. PMID:22339127[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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