1sl3
crystal structue of Thrombin in complex with a potent P1 heterocycle-Aryl based inhibitor
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| , resolution 1.81Å | |||||||
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| Ligands: | |||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
OverviewOverview
In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1SL3 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors., Young MB, Barrow JC, Glass KL, Lundell GF, Newton CL, Pellicore JM, Rittle KE, Selnick HG, Stauffer KJ, Vacca JP, Williams PD, Bohn D, Clayton FC, Cook JJ, Krueger JA, Kuo LC, Lewis SD, Lucas BJ, McMasters DR, Miller-Stein C, Pietrak BL, Wallace AA, White RB, Wong B, Yan Y, Nantermet PG, J Med Chem. 2004 Jun 3;47(12):2995-3008. PMID:15163182
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