Computer system and process for identifying a charge distribution which minimizes electrostatic contribution to binding at binding between a ligand and a molecule in a solvent and uses thereof

Abstract

The present computer-implemented process involves a methodology for determining properties of ligands which in turn can be used for designing ligands for binding with protein or other molecular targets, for example, HIV targets. The methodology defines the electrostatic complement for a given target site and geometry. The electrostatic complement may be used with steric complement for the target site to discover ligands through explicit construction and through the design or bias of combinatorial libraries. The definition of an electrostatic complement, i.e., the optimal tradeoff between unfavorable desolvation energy and favorable interactions in the complex, has been discovered to be useful in ligand design. This methodology essentially inverts the design problem by defining the properties of the optimal ligand based on physical principles. These properties provide a clear and precise standard to which trial ligands may be compared and can be used as a template in the modification of existing ligands and the de novo construction of new ligands. The electrostatic complement for a given target site is defined by a charge distribution which minimizes the electrostatic contribution to binding at the binding sites on the molecule in a given solvent. One way to represent the charge distribution in a computer system is as a set of multipoles. By identifying molecules having point charges that match this optimum charge distribution, the determined charge distribution may be used to identify ligands, to design drugs, and to design combinatorial libraries.