X-RAY AND MOLECULAR MODELLING STUDIES OF NEW POTENTIAL ALDOSE REDUCTASE INHIBITORS. D. Tranqui⁽¹⁾, M. Cussac⁽²⁾, P. Fresneau⁽²⁾, G. Leclerc⁽²⁾, and A.Vegas⁽³⁾, ⁽¹⁾Lab. de Cristallographie-CNRS associé à l' UJF, BP 166, 38042 Grenoble Cedex, France, ⁽²⁾Lab. de Chimie Therapeutique et Organique - Groupe. de Pharmacochimie Moléculaire, UFR de Pharmacie de Grenoble, UJF, BP 138, 38243 Meylan, France. ⁽³⁾Instituto Rocasolano, CSIC, Serrano, 119, E-28006, Madrid, Spain

Several derivatives of 5-(2-Naphtylmethylene)-4-oxo-2-thioxothiazolidin-3-yl acetic, NOTA, were identified as potential inhibitors of aldose reductase. The 1-OCH₃ substituted form of NOTA have been observed to have an inhibitor-aldose-reductase activity one order better than that of the non-substituted derivative. Attempts to model inhibitor-enzyme interaction using the geometry-and-energy-optimised atomic co-ordinates of NOTA, showed the non-substituted form of NOTA fitted snugly in the hydrophobic active site of aldose reductase while binding of the substituted form and aldose reductase may require substantial conformational changes of the latter.

These results incite us to verify the geometry of NOTA molecules used in the previous modelling studies. Single crystals of NOTA were grown and their crystal and molecular structure determined^(*). X-ray structural features of both forms of NOTA are reported and their marked differences with those of molecular mechanic models are highlighted and discussed in terms of molecular packing force and molecule-solvent interaction.

Calculated ([[Delta]]H) for both models shows that they are each other energetically accessible suggesting our docking results using the molecular mechanic model of NOTA remain valid. Preliminary modelling results of inhibitor-enzyme interaction using the X-ray structure model of NOTA appear to confirm this point. Possible hydrophobic interaction scheme of NOTA with aldose reductase is proposed. ^(*)Space group P , a = 7.320(5), b = 8.307(5), c = 16.399(6) Å, [[alpha]] = 81.23(7)[[ring]], [[beta]] = 98.52(6)[[ring]], [[gamma]] = 104.46(8)[[ring]], R-factor = 0.05 and Space group C2/c, a = 34.199(9), b = 5.222(3), c = 23.178(8) Å, [[beta]] = 98.51(6)[[ring]], R-factor = 0.06 for substituted and non-substituted derivatives, respectively.