Desolvation penalty

A summary of properties for indirubin-3 -monoxime is given in Table 6. The molecule is flat, has a moderate logD and acidic character which leads to acceptable predicted solubility. Although the number of H-bond donor groups is quite large (n = 3), it is likely that a tautomeric form in which the hydroxy indole is intramolecularly bonded to the indole nitrogen would be favoured and, if so, this would lead to improved permeability and less desolvation penalty. The PSA is moderate (74 A ) and the predicted brain-plasma ratio [82] is 0.3 (likely... 

From these results, it is clear that a stable intramolecular salt bridge can only form if the intervening water molecules can be dragged out, which involves overcoming a large desolvation barrier. Owing to this desolvation penalty, the structural motif with a stable turn composed of the residues and a preformed D23-K28 contact... 

Solvation free energy calculations predict the energetic cost of desolvation in the binding process and, therefore, help optimize the ligand by highlighting structural changes that minimize the desolvation penalty. 

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