This low hit rate has limited the usage of HTS to research programs capable of screening large compound libraries. However, although traditional HTS often results in multiple hit compounds, some of which are capable of being modified into a lead and later a novel therapeutic, the hit rate for HTS is often extremely low. The method has the advantage of requiring minimal compound design or prior knowledge, and technologies required to screen large libraries have become more efficient.

This brute force approach relies on automation to screen high numbers of molecules in search of those that elicit the desired biologic response. Although progress was being made in CADD, the potential for high-throughput screening (HTS) had begun to take precedence as a means for finding novel therapeutics. Some have credited this as being the start of intense interest in the potential for computer-aided drug design (CADD). On October 5, 1981, Fortune magazine published a cover article entitled the “Next Industrial Revolution: Designing Drugs by Computer at Merck” ( Van Drie, 2007). Finally, computational methods for toxicity prediction and optimization for favorable physiologic properties are discussed with successful examples from literature. In addition, important tools such as target/ligand data bases, homology modeling, ligand fingerprint methods, etc., necessary for successful implementation of various computer-aided drug discovery/design methods in a drug discovery campaign are discussed. We review widely used ligand-based methods such as ligand-based pharmacophores, molecular descriptors, and quantitative structure-activity relationships. Ligand-based methods use only ligand information for predicting activity depending on its similarity/dissimilarity to previously known active ligands.

The article discusses theory behind the most important methods and recent successful applications. Structure-based approaches include ligand docking, pharmacophore, and ligand design methods. Structure-based methods are in principle analogous to high-throughput screening in that both target and ligand structure information is imperative. These methods are broadly classified as either structure-based or ligand-based methods. Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades.

Cat data link code 324 05