INVESTIGATIONS OF NEUROTROPHIC INHIBITORS OF FK506 BINDING-PROTEIN VIA MONTE-CARLO SIMULATIONS

The binding and solution-phase properties of six inhibitors of FK506 b inding protein (FKBP12) were investigated using free energy perturbati on techniques in Monte Carlo statistical mechanics simulations. These nonimmunosuppressive molecules are of current interest for their neuro trophic activity when bound to FKBP12 as well as for their potential a s building blocks for chemical inducers of protein dimerization. Relat ive binding affinities were computed and analyzed for ligands differin g by a phenyl ring, an external phenyl or pyridyl substituent, and a p ipecolyl or prolyl ring. Such results are, in general, valuable for in hibitor optimization and, in the present case, bring into question som e of the previously reported binding data.