%0 Journal Article %A Gregory Sliwoski %A Sandeepkumar Kothiwale %A Jens Meiler %A Edward W. Lowe, Jr. %E Eric L. Barker %T Computational Methods in Drug Discovery %D 2014 %R 10.1124/pr.112.007336 %J Pharmacological Reviews %P 334-395 %V 66 %N 1 %X Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades. These methods are broadly classified as either structure-based or ligand-based methods. Structure-based methods are in principle analogous to high-throughput screening in that both target and ligand structure information is imperative. Structure-based approaches include ligand docking, pharmacophore, and ligand design methods. The article discusses theory behind the most important methods and recent successful applications. Ligand-based methods use only ligand information for predicting activity depending on its similarity/dissimilarity to previously known active ligands. We review widely used ligand-based methods such as ligand-based pharmacophores, molecular descriptors, and quantitative structure-activity relationships. 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. Finally, computational methods for toxicity prediction and optimization for favorable physiologic properties are discussed with successful examples from literature. %U https://pharmrev.aspetjournals.org/content/pharmrev/66/1/334.full.pdf