Title of article :
Probing the ultra-high resolution structure of aldose reductase with molecular modelling and noncovalent mass spectrometry Original Research Article
Author/Authors :
Connie Darmanin، نويسنده , , Guillaume Chevreux، نويسنده , , Noelle Potier، نويسنده , , Alain Van-Dorsselaer، نويسنده , , Isabelle Hazemann، نويسنده , , Alberto Podjarny، نويسنده , , Ossama El-Kabbani، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2004
Pages :
10
From page :
3797
To page :
3806
Abstract :
Aldose reductase, the first and rate-limiting enzyme of the polyol pathway, is a target for drug design for the treatment of diabetes complications. The structures of aldose reductase in complex with the cyclic imide inhibitors Fidarestat and Minalrestat were recently determined at ultra-high resolution (Proteins 2004, 55, 805). We have used the detailed structural information revealed at atomic resolution, including the assignment of protonation states for the inhibitors and active site residues, together with molecular modelling and noncovalent mass spectrometry to characterise the type and strength of the interactions between the enzyme and the inhibitors, and to attempt the design of novel potential inhibitors with enhanced binding energies of the complexes. The VC50 values measured by mass spectrometry (accelerated voltage of ions needed to dissociate 50% of a noncovalent complex in the gas phase) for the aldose reductase inhibitors correlate with the IC50 values (concentration of inhibitor giving 50% inhibition in solution) and with the electrostatic binding energies calculated between the active site residues Tyr48, His110 and Trp111 and the inhibitors, suggesting that electrostatic interactions play a major role in inhibitor binding. Our molecular modelling and design studies suggest that the replacement of the fluorine atom in Minalrestatʹs bromo-fluorobenzyl group with nitro, amide and carboxylate functional groups enhanced the predicted net binding energies of the complexes by 16%, 31% and 68%, respectively. When the carbamoyl group of Fidarestat was replaced with a nitro, 4-hydroxyl phenyl and carboxylate functional groups, the predicted net binding energies of the complexes were enhanced by 13%, 34% and 46%, respectively.
Keywords :
mass spectrometry , Aldose reductase , molecular modelling , drug design , Ultra-high resolution , Enzyme inhibitors
Journal title :
Bioorganic and Medicinal Chemistry
Serial Year :
2004
Journal title :
Bioorganic and Medicinal Chemistry
Record number :
1303160
Link To Document :
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