In search of negative allosteric modulators of biological targets.

The value of using negative allosteric modulators of protein function in therapeutic treatment of human diseases is becoming more apparent. Many current screening paradigms, however, are not consciously designed to discover negative allosteric modulators, and those that are serendipitously discovered can be easily overlooked during the hit-picking process. The conditions necessary for the discovery of negative allosteric modulators in a high-throughput screen are quite reasonable and simple to implement, generally requiring a consideration of the ligand concentration in a screen. Other considerations in the screening for negative allosteric modulators can be derived from an analysis of simple kinetic schemes that describe the interactions of ligands and modulators with different protein targets.