2pk6
From Proteopedia
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|PDB= 2pk6 |SIZE=350|CAPTION= <scene name='initialview01'>2pk6</scene>, resolution 1.450Å | |PDB= 2pk6 |SIZE=350|CAPTION= <scene name='initialview01'>2pk6</scene>, resolution 1.450Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=O33:(4R)-N-[(1S,2R)-2-HYDROXY-2,3-DIHYDRO-1H-INDEN-1-YL]-3-[(2S,3S)-2-HYDROXY-3-({N-[(ISOQUINOLIN-5-YLOXY)ACETYL]-S-METHYL-L-CYSTEINYL}AMINO)-4-PHENYLBUTANOYL]-5,5-DIMETHYL-1,3-THIAZOLIDINE-4-CARBOXAMIDE'>O33 | + | |LIGAND= <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=O33:(4R)-N-[(1S,2R)-2-HYDROXY-2,3-DIHYDRO-1H-INDEN-1-YL]-3-[(2S,3S)-2-HYDROXY-3-({N-[(ISOQUINOLIN-5-YLOXY)ACETYL]-S-METHYL-L-CYSTEINYL}AMINO)-4-PHENYLBUTANOYL]-5,5-DIMETHYL-1,3-THIAZOLIDINE-4-CARBOXAMIDE'>O33</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= gag-pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1]) | |GENE= gag-pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2pk6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pk6 OCA], [http://www.ebi.ac.uk/pdbsum/2pk6 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2pk6 RCSB]</span> | ||
}} | }} | ||
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[[Category: Kiso, Y.]] | [[Category: Kiso, Y.]] | ||
[[Category: Lafont, V.]] | [[Category: Lafont, V.]] | ||
| - | [[Category: GOL]] | ||
| - | [[Category: O33]] | ||
[[Category: protease complex]] | [[Category: protease complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:37:03 2008'' |
Revision as of 01:37, 31 March 2008
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| , resolution 1.450Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Gene: | gag-pol (Human immunodeficiency virus 1) | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of HIV-1 Protease (Q7K, L33I, L63I) in Complex with KNI-10033
Overview
A common strategy to improve the potency of drug candidates is to introduce chemical functionalities, like hydrogen bond donors or acceptors, at positions where they are able to establish strong interactions with the target. However, it is often observed that the added functionalities do not necessarily improve potency even if they form strong hydrogen bonds. Here, we explore the thermodynamic and structural basis for those observations. KNI-10033 is a potent experimental HIV-1 protease inhibitor with picomolar affinity against the wild-type enzyme (K(d) = 13 pm). The potency of the inhibitor is the result of favorable enthalpic (DeltaH = -8.2 kcal/mol) and entropic (-TDeltaS = -6.7 kcal/mol) interactions. The replacement of the thioether group in KNI-10033 by a sulfonyl group (KNI-10075) results in a strong hydrogen bond with the amide of Asp 30B of the HIV-1 protease. This additional hydrogen bond improves the binding enthalpy by 3.9 kcal/mol; however, the enthalpy gain is completely compensated by an entropy loss, resulting in no affinity change. Crystallographic and thermodynamic analysis of the inhibitor/protease complexes indicates that the entropy losses are due to a combination of conformational and solvation effects. These results provide a set of practical guidelines aimed at overcoming enthalpy/entropy compensation and improve binding potency.
About this Structure
2PK6 is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
Reference
Compensating enthalpic and entropic changes hinder binding affinity optimization., Lafont V, Armstrong AA, Ohtaka H, Kiso Y, Mario Amzel L, Freire E, Chem Biol Drug Des. 2007 Jun;69(6):413-22. PMID:17581235
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