4lb3: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
[[4lb3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LB3 OCA]. <br> | [[4lb3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LB3 OCA]. <br> | ||
<b>Related:</b> [[1us0|1us0]], [[2iki|2iki]], [[4lau|4lau]], [[4laz|4laz]], [[4lb4|4lb4]], [[4lbr|4lbr]], [[4lbs|4lbs]]<br> | <b>[[Ligand|Ligands:]]</b> <scene name='pdbligand=M15:{5-CHLORO-2-[(2-FLUORO-4-IODOBENZYL)CARBAMOYL]PHENOXY}ACETIC+ACID'>M15</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene><br> | ||
<b>[[Related_structure|Related:]]</b> [[1us0|1us0]], [[2iki|2iki]], [[4lau|4lau]], [[4laz|4laz]], [[4lb4|4lb4]], [[4lbr|4lbr]], [[4lbs|4lbs]]<br> | |||
<b>Activity:</b> <span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span><br> | <b>Activity:</b> <span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span><br> | ||
<b>Resources:</b> <span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4lb3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lb3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lb3 RCSB], [http://www.ebi.ac.uk/pdbsum/4lb3 PDBsum]</span><br> | |||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
In this paper, we studied a designed series of aldose reductase (AR) inhibitors. The series was derived from a known AR binder, which had previously been shown to form a halogen bond between its bromine atom and the oxygen atom of the Thr-113 side chain of AR. In the series, the strength of the halogen bond was modulated by two factors, namely bromine-iodine substitution and the fluorination of the aromatic ring in several positions. The role of the single halogen bond in AR-ligand binding was elucidated by advanced binding free energy calculations involving the semiempirical quantum chemical Hamiltonian. The results were complemented with ultrahigh-resolution X-ray crystallography and IC50 measurements. All of the AR inhibitors studied were shown by X-ray crystallography to bind in an identical manner. Further, it was demonstrated that it was possible to decrease the IC50 value by about 1 order of magnitude by tuning the strength of the halogen bond by a monoatomic substitution. The calculations revealed that the protein-ligand interaction energy increased upon the substitution of iodine for bromine or upon the addition of electron-withdrawing fluorine atoms to the ring. However, the effect on the binding affinity was found to be more complex due to the change of the solvation/desolvation properties within the ligand series. The study shows that it is possible to modulate the strength of a halogen bond in a protein-ligand complex as was designed based on the previous studies of low-molecular-weight complexes. | In this paper, we studied a designed series of aldose reductase (AR) inhibitors. The series was derived from a known AR binder, which had previously been shown to form a halogen bond between its bromine atom and the oxygen atom of the Thr-113 side chain of AR. In the series, the strength of the halogen bond was modulated by two factors, namely bromine-iodine substitution and the fluorination of the aromatic ring in several positions. The role of the single halogen bond in AR-ligand binding was elucidated by advanced binding free energy calculations involving the semiempirical quantum chemical Hamiltonian. The results were complemented with ultrahigh-resolution X-ray crystallography and IC50 measurements. All of the AR inhibitors studied were shown by X-ray crystallography to bind in an identical manner. Further, it was demonstrated that it was possible to decrease the IC50 value by about 1 order of magnitude by tuning the strength of the halogen bond by a monoatomic substitution. The calculations revealed that the protein-ligand interaction energy increased upon the substitution of iodine for bromine or upon the addition of electron-withdrawing fluorine atoms to the ring. However, the effect on the binding affinity was found to be more complex due to the change of the solvation/desolvation properties within the ligand series. The study shows that it is possible to modulate the strength of a halogen bond in a protein-ligand complex as was designed based on the previous studies of low-molecular-weight complexes. | ||