The importance of molecular design principles in delivering high quality pharmaceutical candidates

High throughput screening of large chemical libraries of compounds is a proven way to identify novel chemical entities that target a biological system of interest. This technology is being used by industry and a growing number of academic screening centers for drug discovery campaigns. Unfortunately, many of the components of screening libraries have poor drug-like properties and require optimization. Typical components of a screening hit that need to be optimized include water solubility, reduced potential for toxicity, and metabolic stability. Presently, methods to alter individual molecular properties are not well elucidated. This chapter will discuss the molecular design principles that have been used successfully to alter the physiochemical properties of molecules through medicinal chemistry. Insights will be provided into the differences in approaches needed for optimization of a biological probe for target validation versus that of a hit to lead campaign, the design of more drug-like libraries, and the over-reliance of potency in optimization campaigns.