Exploiting QSAR models in lead optimization.

QSAR models can play a vital role in both the opening phase and the endgame of lead optimization. In the opening phase, there is often a large quantity of data from high-throughput screening (HTS), and potential leads need to be selected from several distinct chemotypes. In the endgame, the throughput of the final, critical ADMET and pharmacokinetic assays is often not sufficient to allow full experimental characterization of all the structures in the available time. A considerable amount of the current research toward new QSAR models is based on the modeling of the general ADMET phenomena, with the aim of constructing globally applicable models. The process to construct QSAR models is relatively straightforward; however, it is also simple to build misleading, or even incorrect, models. This review considers the key developments in the field of QSAR modeling: how QSAR models are constructed, how they can be validated, their reliability and their applicability. If applied carefully and appropriately, the QSAR technique has a valuable role to play during lead optimization.