Inside the Hsp90 inhibitors binding mode through induced fit docking

During the last few decades, the development of new anticancer strategies had to face the instability of many tumors, occurring when the genetic plasticity of cells produces new drug-resistant cancers. It has been shown that a chaperone protein, he at shock protein 90 (Hsp90), is one of the fundamental factors involved in the cell response to stresses, and its role in many biochemical pathways has been demonstrated. Thus, the inhibition of Hsp90 represents a new target of antitumor therapy, since it may influence many specific signaling pathways. The natural antibiotic Geldanamycin is the first Hsp90 inhibitor that has been identified. Nevertheless, more potent and water-soluble small molecules are currently in development, and many X-ray crystallographic structures of Hsp90-inhibitor complexes are available for drug discovery purposes. Here we used the complexes of Hsp90 with eight different ligands, belonging to several chemical classes, to perform molecular docking experiments, using a novel technique called induced fit. Through this approach, it was possible to take into account the flexibility of the residues in the active site and to maintain a high level of precision in docking algorithms. The results allowed to identify several conserved residues involved in the interaction between Hsp90 and its inhibitor. Moreover, the exposition of the active site to solvent allows many water molecules to insert within the complex, providing additional hydrogen and polar interactions. Our models also provided template structures for further experiments and reproduces with a good degree of reliability, the conformations of the inhibitors as observed in experimental structures. (C) 2008 Elsevier Inc. All rights reserved.