Advanced Review Molecular interaction fields in drug discovery: recent advances and future perspectives Anna Artese, 1 Simon Cross, 2 ∗ Giosu ` e Costa, 1 Simona Distinto, 3 Lucia Parrotta, 1 Stefano Alcaro, 1 Francesco Ortuso 1 and Gabriele Cruciani 4 Drug discovery is a highly complex and costly process, and in recent years, the pharmaceutical industry has shifted from traditional to genomics- and proteomics-based drug research strategies. The identification of druggable target sites, promising hits, and high quality leads are crucial steps in the early stages of drug discovery projects. Pharmacokinetic (PK) and drug metabolism profil- ing to optimize bioavailability, clearance, and toxicity are increasingly important areas to prevent costly failures in preclinical and clinical studies. The integra- tion of a wide variety of technologies and expertise in multidisciplinary research teams combining synergistic effects between experimental and computational approaches on the selection and optimization of bioactive compounds to pass these hurdles is now commonplace, although there remain challenging areas. Molecular interaction fields (MIFs) are widely used in a range of applications to support the discovery teams, characterizing molecules according to their favor- able interaction sites and therefore enabling predictions to be made about how molecules might interact. The utility of MIF-based in silico approaches in drug design is extremely broad, including approaches to support experimental design in hit-finding, lead-optimization, physicochemical property prediction and PK modeling, drug metabolism prediction, and toxicity. C  2013 John Wiley & Sons, Ltd. How to cite this article: WIREs Comput Mol Sci 2013, 00: 1–20 doi: 10.1002/wcms.1150 INTRODUCTION T he discovery and development of a new drug is an expensive and time-consuming process; thera- peutic effects and hazards to health are assessed using The authors have declared no conflicts of interest in relation to this article. ∗ Correspondence to: simon@moldiscovery.com 1 Dipartimento di Scienze della Salute, Universit ` a degli Studi “Magna Græcia” di Catanzaro, Campus “S. Venuta”, Viale Europa, Catanzaro, Italy 2 Molecular Discovery Ltd., Pinner, Middlesex, London, United Kingdom 3 Dipartimento di Scienze della Vita e dell’Ambiente, Universit ` a di Cagliari, Cagliari, Italy 4 Laboratory for Chemometrics and Cheminformatics, Chemistry Department, University of Perugia, Perugia, Italy DOI: 10.1002/wcms.1150 a series of experimental and in vivo tests. However, usage of animal models is often subject to ethical (and financial) considerations, and therefore alternative methods are being developed to reduce the require- ment of animals in testing. In particular, drug discov- ery has moved toward more rational strategies based on our increasing understanding of protein–ligand in- teractions. The combination of the available knowl- edge of a large number of three-dimensional pro- tein structures with hundreds of thousands of small- molecules has attracted the attention of scientists from all over the world for the application of structure- and ligand-based drug design approaches. In silico methods are often implemented because of their lower cost and ability to help medicinal chemists prioritize which compounds to make; they have been shown to have made a significant contribution to the identifi- cation and development of effective drugs from new Volume 00, xx/xx 2013 1 C  2013 John Wiley & Sons, Ltd.