3D QSAR in modern drug design

The belief that there is a direct relationship between chemical structure and biological activity of therapeutic agents is fundamental to the field of medicinal chemistry. Indeed, the efforts of early medicinal chemists focused on well-defined structural modifications to active lead compounds as molecules were developed into drugs. The relationship between chemical properties like solvent partitioning and biological activity was recognized over a century ago [1]. Almost 40 years ago, Hansch, Fujita and co-workers invented the field of Quantitative Structure-Activity Relationships (QSAR) [2]. In this approach hole molecule parameters such as LogPo/w (the partition coefficient for 1-octanol/water partitioning),[3] molar refractivity, shape and topology indices [4], etc. for groups of related compounds are statistically correlated with measures of biological activity to obtain a QSAR equation. This equation relates easy to measure (or predict/calculate) values for molecules to the more difficult to measure biological activities. Once a QSAR is obtained, verified and found to be “predictive,” the biological activity for new chemical entities that may or may not exist can easily be predicted. Numerous success stories from QSAR over the past four decades validate the fundamental relationship between structure and activity.