Literature summary for 1.1.1.21 extracted from

Rechlin, C.; Scheer, F.; Terwesten, F.; Wulsdorf, T.; Pol, E.; Fridh, V.; Toth, P.; Diederich, W.E.; Heine, A.; Klebe, G.
Price for opening the transient specificity pocket in human aldose reductase upon ligand binding structural, thermodynamic, kinetic, and computational analysis (2017), ACS Chem. Biol., 12, 1397-1415 .

Crystallization (Commentary)

Crystallization (Comment)	Organism
structures in complex with 2-carbamoyl-phenoxy-acetic acid derivatives. Opening of the protein-binding pocket occurs only once an appropriate substituent is attached to the parent substrate scaffold. Up to five water molecules entering the opened pocket cannot stabilize this state. Sole substitution with a benzyl group stabilizes the opened state, and the energetic barrier for opening is estimated to be about 5 kJ/mol. Additional decoration of the pocket-opening benzyl substituent with a nitro group results in a huge enthalpy-driven potency increase. An isosteric carboxylic acid group reduces the potency 1000fold, and binding occurs without pocket opening	Homo sapiens

Crystallization (Comment)

Organism

structures in complex with 2-carbamoyl-phenoxy-acetic acid derivatives. Opening of the protein-binding pocket occurs only once an appropriate substituent is attached to the parent substrate scaffold. Up to five water molecules entering the opened pocket cannot stabilize this state. Sole substitution with a benzyl group stabilizes the opened state, and the energetic barrier for opening is estimated to be about 5 kJ/mol. Additional decoration of the pocket-opening benzyl substituent with a nitro group results in a huge enthalpy-driven potency increase. An isosteric carboxylic acid group reduces the potency 1000fold, and binding occurs without pocket opening

Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
(2-carbamoyl-5-fluorophenoxy)acetic acid	the carboxamide nitrogen can undergo a further H-bond to the additionally recruited water molecule W2 that in turn mediates H-bonded contacts involving the additional water molecule W3 to the amide bonds next to Leu300. Using water molecules W2 and W3 as mediating partners, the compound forms additional polar contacts to the protein	Homo sapiens
(3-sulfanyl[1,2,5]triazepino[4,3-b]indol-6(3H)-yl)acetic acid	-	Homo sapiens
3-[2-(carboxymethoxy)-4-fluorobenzamido]benzoic acid	the ligand directs its acid group toward the surrounding solvent and accommodates the hydrophobic cleft adjacent to the sealed specificity pocket	Homo sapiens
[(3-[[(3-nitrophenyl)methyl]carbamoyl][1,1'-biphenyl]-4-yl)oxy]acetic acid	-	Homo sapiens
[2-(ethynylcarbamoyl)-5-fluorophenoxy]acetic acid	the ligand exhibits a terminal pi-electron rich substituent at the amide function, which fills the cleft between Leu300 and Trp219 next to the sealed specificity pocket	Homo sapiens
[2-[(1,3-benzothiazol-2-yl)carbamoyl]-5-fluorophenoxy]acetic acid	an H-bond is formed between the backbone Leu300NH group and the nitrogen atom of the benzothiazolyl moiety	Homo sapiens
[5-fluoro-2-(phenylcarbamoyl)phenoxy]acetic acid	ligand is among the weakest of the known ALR2 binders that open the specificity pocket	Homo sapiens
[5-fluoro-2-[(3-nitrophenyl)carbamoyl]phenoxy]acetic acid	the ligand opens the specificity pocket with its terminal benzyl moiety and places the meta attached nitro group deeply in the transient pocket	Homo sapiens
[5-fluoro-2-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)carbamoyl]phenoxy]acetic acid	-	Homo sapiens

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P15121	-	-