Advanced in silico techniques in Rational Drug Design. Application to immunophilin ligands.

This thesis presents the application of advanced molecular dynamics techniques as "tool" in design of small molecules that bind to protein targets. In the first part, our initial goal was to understand the factors governing the molecular recognition of FKBP12 binding domain, through the study of the conformational space of known ligands with disparate affinity costants. In the second part of this thesis, results of the former part, were applied to in silico design of new high-affinity ligands. Subsequent synthesis and characterization confirm that all novel ligands have affinity in the nano molar range. Moreover, among these ligands, the compound Elte378 is, for our knowledge, the most potent synthetic inhibitor of FKBP12 to date.