Abstract: Centrifugation is used to induce and/or enhance binding between macromolecular targets and either small-molecule ligands or larger biomolecules as single entities or mixtures. With the enhanced binding, the method of the invention permits detection of ligands that bind to target substances and improve the design of ligands. The process relies on centrifugal force to establish a differential and selective concentration gradient between macromolecular therapeutic targets and the desired ligands. Once formed, the information about the self-sorting binding events is derived by analyzing the differential gradient of macromolecules and ligands in situ or by fractionating the gradient into individual samples for independent analysis. A variety of methods or combinations thereof, can be used to look for enhanced levels of bound ligands.