Drug Discovery Today  Volume 19, Number 11  November 2014 REVIEWS REACH and in silico methods: an attractive opportunity for medicinal chemists Orazio Nicolotti 1 , Emilio Benfenati 2 , Angelo Carotti 1 , Domenico Gadaleta 1 , Andrea Gissi 1 , Giuseppe Felice Mangiatordi 1 and Ettore Novellino 3 1 Dipartimento di Farmacia-Scienze del Farmaco, Universita ` degli Studi di Bari ‘Aldo Moro’, Via E. Orabona 4, 70125 Bari, Italy 2 IRCCS-Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via La Masa 19, 20156 Milano, Italy 3 Dipartimento di Farmacia – Universita ` degli Studi di Napoli ‘Federico II’, Via D. Montesano 49, 80131 Napoli, Italy REACH, the most ambitious chemical legislation in the world, provides unprecedented opportunities for medicinal chemists. Companies must report (eco)toxicological information about their chemicals, disseminated to the public domain by the European Chemicals Agency after their registration. The availability of this wealth of new toxicological data, together with the promotion of REACH of in silico methods, appoints medicinal chemists to a leading role in the regulatory hazard assessment process. In fact, Quantitative Structure–Activity Relation ship (QSAR) models and predictive toxicology have been applied in drug design and development for decades. Here, we discuss toxicological endpoints and areas where further development is needed to provide an enlightened appraisal of this attractive new opportunity. Introduction Currently, approximately 30 million chemical substances are esti- mated to be on the market [1]. They include food coloring and preservatives, varnishes, pesticides, and, of course, drugs. In De- cember 2006, the European Community (EC) issued a new regula- tion concerning the Registration, Evaluation, Authorization and restriction of Chemicals [2]. Known as REACH, this legislation brought about a revolution in the chemical regulatory world. For the first time, the responsibility of proving the safety of chemicals was moved from public authorities to industry. The main aim of REACH is: ‘[. . .] to ensure a high level of protection of human health and the environment, including the promotion of alterna- tive methods for assessment of hazards of substances, as well as the free circulation of substances on the internal market while en- hancing competitiveness and innovation. [. . .]’ [2]. REACH is now the paradigm of an intentional shift toward a more responsible, sustainable, and green use of chemicals. These objectives are inspired by the principle ‘No data – no market’ and are pursued through the authorization and restriction processes in place for the most hazardous substances. Each chemical, manufactured or imported in Europe in a quan- tity above 1 ton per year, has to be registered to the European Chemicals Agency (ECHA) by submitting a dossier describing physicochemical, biological, and toxicological properties (all to- gether called endpoints; Fig. 1). Chemicals whose uses are covered by other EU legislation (e.g. food additives or medicines) are partially exempted from REACH. However, precursors in the syn- thesis of the drugs or medicines with additional uses need to be registered. The information requirements and the deadline for registration depend on the level of concern raised by the sub- stance. For carcinogens, mutagens, and reproductive toxicants (CMRs), substances highly toxic to aquatic organisms, and large production volume chemicals, the requirements are stricter. Not surprisingly, international mass media have welcomed REACH as ‘the most important legislation in European Union in 20 years’ (BBC News, 28 November 2005) and ‘the strictest law to date regulating chemical substances’ (San Francisco Chroni- cle, 14 December 2006). Other countries, such as China, Turkey, Japan, and, very recently, South Korea, are adopting REACH-type regulations, proving its success. The USA is also working in this direction [3]. By contrast, REACH has also been (and still is) subject to strong criticism from different stakeholders. In particular, industry Reviews  POST SCREEN Corresponding author:. Nicolotti, O. (orazio.nicolotti@uniba.it) 1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.06.027 www.drugdiscoverytoday.com 1757