Methods of calculating differences of binding affinities between congeneric pairs of ligands by way of a displaced solvent functional

US7756674B2 · kind B2 · utility

Assignee

• The Trustees of Columbia University in the City of New York · US

Inventors

• Thomas Young · New York, US
• Robert Abel · Brooklyn, US
• Richard A. Friesner · New York, US
• Bruce J. Berne · Dobbs Ferry, US

Key dates

• Filing date: Nov 5, 2007
• Grant date: Jul 13, 2010
• Expiry date: Feb 22, 2028

Classification

• Technology area (CPC G): Physics
• CPC primary: G16C20/50
• WIPO field: Computer technology
• WIPO sector: Electrical engineering

Abstract

Described is a technique to exhaustively enumerate the thermodynamic properties of the water molecules solvating the active site of a protein in its apostate and calculate the relative binding affinities of congeneric compounds that bind to this protein. The subject matter includes sampling the configurations of the solvating water in the active site; extracting the thermodynamic information about the solvating water from these configurations by clustering the observed water configurations into regions of high water occupancy (e.g., “hydration sites”), computing the average system interaction energies of water molecules occupying the various hydrations sites, computing excess entropies of water molecules occupying the hydration sites; constructing a 3 dimensional hydration thermodynamics map of the protein active site; and computing relative binding affinities of congeneric ligands based on the principle that tighter binding ligands can displace more entropically structured and energetically depleted hydration sites from the active site into the bulk fluid.