COMPUTER METHOD UTILIZING FREE ENERGY CALCULATIONS FOR LIGAND DESIGN AND THE PREDICTION OF BINDING TARGETS

摘要

A computer-based method for the identification of binding targets in proteinsandother macromolecules. More particularly, the invention includes an algorithmaimedat predicting binding targets in proteins. This algorithm, named Woolford,requiresknowledge of the high resolution structure of the protein but no knowledge ofthe locationor identity of natural binding sites or ligands. Binding targets in theprotein are identifiedand classified according to their expected optimal affinities. Binding targetscan belocated at the protein surface or at internal surfaces that become exposed asa resultof partial unfolding, conformational changes, subunit dissociation, or otherevents. Theentire protein is mapped according to the binding potential of its constituentatoms. Oncebinding targets are identified, optimal ligands are designed and progressivelybuilt by theaddition of individual atoms that complement structurally and energeticallythe selectedtarget. This algorithm is expected to have significant applications instructure-based drugdesign since it allows: 1) identification of binding targets in proteins; 2)identificationof additional targets if the primary target is known; 3) design of ligandmolecules withoptimal binding affinities for the selected target; and 4) refinement of leadcompounds bydefining the location and nature of chemical groups for optimal bindingaffinity.