A lead compound may arise from a variety of different sources. Lead compounds are found by characterizing natural products, employing combinatorial chemistry, or by molecular modeling as in rational drug design. Chemicals identified as hits through high-throughput screening may also become lead compounds. Once a lead compound is selected it must undergo lead optimization, which involves making the compound more "drug-like." This is where Lipinski's rule of five comes into play, sometimes also referred to as the "Pfizer rule" or simply as the "rule of five." Other factors, such as the ease of scaling up the manufacturing of the chemical, must be taken into consideration.