Estimation of the binding affinities of FKBP12 inhibitors using a linear response method

A series of non-immunosuppressive inhibitors of FK506 binding protein (FKBP 12) are investigated using Monte Carlo statistical mechanics simulations. T hese small molecules may serve as scaffolds for chemical inducers of protei n dimerization, and have recently been found to have FKBP12-dependent neuro trophic activity. A linear response model was developed for estimation of a bsolute binding free energies based on changes in electrostatic and van der Waals energies and solvent-accessible surface areas, which are accumulated during simulations of bound and unbound ligands. With average errors of 0. 5 kcal/mol, this method provides a relatively rapid way to screen the bindi ng of ligands while retaining the structural information content of more ri gorous free energy calculations. (C) 1999 Elsevier Science Ltd. All rights reserved.