Role of Molecular Docking in Computer-Aided Drug Design and Development

2. History Of Cadd

The evolution of CADD began in 1900s when Emiel Fischer (in 1894) and later Paul Ehlrich (in 1909) propagated the concept of receptors and lock and key mechanism (Fischer, 1894). Lock and key concept explains the interaction of a drug and its receptor. Just as there are innumerable pairs of lock and key, where each key inserts into a specific lock to open it, drugs are designed to be tailor made for a particular receptor. Depending on the perfection of the design, the drugs its binding capacity of the drugs with the receptor excels. But just as duplicate keys can be made for a single lock, which makes the lock vulnerable, there is a chance that multiple drugs can work on single receptor thereby giving rise to undue side effects. Additionally one drug can also interact with multiple receptors again giving rise to undue side effects. It was Paul Ehlrich, who proposed the concept of “magic bullet” the elusive drug that only bind to the chosen receptor thereby exhibiting no side effects (Elrich P, 1909,1957).

Nearly 70 years later with the advent of quantitative structure activity relationship (QSAR), CADD took its next leap towards advancement. At that time only 2-dimentional medchem properties were considered and it was much later that the 3-dimentional properties came into the picture. Gradually, with the evolution of the concepts of molecular biology, protein X-ray crystallography (refer Figure 1) and multidimensional nuclear magnetic resonance spectroscopy (NMR), CADD too evolved into a more reliable and viable strategy in drug discovery.

Figure 1.

Flowsheet of the operations in CADD

Figure 2.

PDB protein structure growth per annum graph that displays the number of searchable protein structures per year

Advancements in high performance computing, availability of 3-dimensional structure of important pharmaceutical targets, has opened new possibilities for computational drug design. An article in Fortune magazine entitled “Next Industrial Revolution: Designing Drugs by Computer at Merck” (Sliwoski et al., 2014; Van Drie, 2007) clearly postulated the beginning of a new era for drug discovery methods involving a bevy of computational approaches.