Investigations of neurotrophic inhibitors of FK506 binding protein via Monte Carlo simulations

J Med Chem. 1998 Oct 8;41(21):3928-39. doi: 10.1021/jm980062o.

Abstract

The binding and solution-phase properties of six inhibitors of FK506 binding protein (FKBP12) were investigated using free energy perturbation techniques in Monte Carlo statistical mechanics simulations. These nonimmunosuppressive molecules are of current interest for their neurotrophic activity when bound to FKBP12 as well as for their potential as building blocks for chemical inducers of protein dimerization. Relative binding affinities were computed and analyzed for ligands differing by a phenyl ring, an external phenyl or pyridyl substituent, and a pipecolyl or prolyl ring. Such results are, in general, valuable for inhibitor optimization and, in the present case, bring into question some of the previously reported binding data.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzene Derivatives / chemistry
  • Benzene Derivatives / metabolism
  • Binding Sites
  • Chickens
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Immunophilins / antagonists & inhibitors*
  • Immunophilins / metabolism
  • Immunosuppressive Agents / metabolism*
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Monte Carlo Method
  • Neurites / drug effects
  • Neurites / physiology
  • Peptidylprolyl Isomerase / antagonists & inhibitors*
  • Pyridines / chemistry
  • Pyridines / metabolism
  • Tacrolimus / metabolism*
  • Tacrolimus Binding Proteins
  • Thermodynamics

Substances

  • Benzene Derivatives
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Ligands
  • Pyridines
  • Tacrolimus Binding Proteins
  • Immunophilins
  • Peptidylprolyl Isomerase
  • Tacrolimus