Ligand design by a combinatorial approach based on

Authors: Erik Evensen Diane JosephMcCarthy Gregory A Weiss Stuart L Schreiber Martin Karplus

Publish Date: 2007/07/27

Volume: 21, Issue: 7, Pages: 395-418

PDF Link

Abstract

Combinatorial synthesis and large scale screening methods are being used increasingly in drug discovery particularly for finding novel lead compounds Although these “random” methods sample larger areas of chemical space than traditional synthetic approaches only a relatively small percentage of all possible compounds are practically accessible It is therefore helpful to select regions of chemical space that have greater likelihood of yielding useful leads When threedimensional structural data are available for the target molecule this can be achieved by applying structurebased computational design methods to focus the combinatorial library This is advantageous over the standard usage of computational methods to design a small number of specific novel ligands because here computation is employed as part of the combinatorial design process and so is required only to determine a propensity for binding of certain chemical moieties in regions of the target molecule This paper describes the application of the Multiple Copy Simultaneous Search MCSS method an active site mapping and de novo structurebased design tool to design a focused combinatorial library for the class II MHC protein HLADR4 Methods for the synthesizing and screening the computationally designed library are presented evidence is provided to show that binding was achieved Although the structure of the proteinligand complex could not be determined experimental results including crossexclusion of a known HLADR4 peptide ligand HA by a compound from the library Computational model building suggest that at least one of the ligands designed and identified by the methods described binds in a mode similar to that of native peptides

Keywords: