A Novel Strategy for Improving Ligand Selectivity in Receptor-Based Drug Design

A major desirable characteristic of many drugs is their ability to interact specifically with only one variety of the target receptor among many others. It is remarkable that, even when accurate three dimensional structures for the target biomolecules are available, there is no wellestablished methodology to describe their differences and use them for the design of selectivelyinteracting compounds. This work presents a novel method that uses multivariate GRID descriptors and principal component analysis (PCA) with the aim of revealing the most relevant structural and physicochemical differences between biomacromolecules related to receptor selectivity. The methodology is described through an exampleinvolving the study of bacterial (Escherichia coli) and recombinant human varieties of the dihydrofolate reductase (EC 1.5.1.3, DHFR) enzyme. This analysis easily unveils the most important regions on these biomolecules which should be taken into consideration for the design of selectively interacting compounds.