802 Current Topics in Medicinal Chemistry, 2012, 12, 802-813 1873-5294/12 $58.00+.00 © 2012 Bentham Science Publishers Computer-Aided Drug Design Methodologies Toward the Design of Anti-Hepatitis C Agents Alejandro Speck-Planche a,b, * and M. Natália D. S. Cordeiro a, * a REQUIMTE/Department of Chemistry and Biochemistry, University of Porto, 4169-007 Porto, Portugal. b Department of Chemistry, Faculty of Natural Sciences, University of Oriente, Patricio Lumumba s/n, 90500 Santiago de Cuba, Cuba. Abstract: Hepatitis C constitutes an infectious disease that causes severe damages to the liver, and is caused by hepatitis C virus. There is no vaccine against this type of disease and the number of people infected continues to grow worldwide. The anti-viral therapy which is currently used is a mixture of interferon alpha-2a with ribavirin, but approximately half of the patients do not respond to therapy. Therefore, it is necessary to search for new compounds with anti-hepatitis C activity. Computer-aided drug design methodologies have been vital in the discovery of candidates to drugs. This review is dedicated to the role of computer-aided drug design methodologies for the development of new anti-hepatitis C agents. In addition, we introduce a QSAR model based on substructural approaches in order to model the anti-hepatitis C activity in vivo. Keywords: Anti-HCV agents, QSAR, 3D-QSAR, structure-based drug design, linear discriminant analysis, fragments. INTRODUCTION Hepatitis C (HC) is an infectious disease that affects the liver. It is caused by the hepatitis C virus (HCV), the only known member of the hepacivirus genus in the family Flaviviridae [1]. Although this infection is often asympto- matic, once established, chronic infection can progress to scarring of the liver (fibrosis), and advanced scarring (cirrho- sis) which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure or other complications of cirrhosis, including liver cancer, and in other cases, life threatening esophageal and gastric varices. Currently HCV infection is thought to be transmitted by parenteral and nosocomial routes and it has been esti- mated that nearly 200 million people worldwide are infected with HCV, being in addition 2-3 million infected per year. HC has thus the potential to be the next pandemic [2, 3]. Spontaneous viral clearance rates are highly variable and between 10-60% of people infected with HCV clear the virus from their bodies during the acute phase as shown by nor- malization in liver enzymes (alanine transaminase (ALT) & aspartate transaminase (AST)), and plasma HCV-RNA clearance (this is known as spontaneous viral clearance). However, persistent infections are common and most pa- tients develop chronic hepatitis C [4]. The prevalence of HC is higher in Asian and African countries, where the health conditions are extremely unfavorable. The worst case is Egypt, country which is believed that HC is linked to a now- discontinued mass-treatment campaign for schistosomiasis, which is endemic in that country [5]. An important factor in HCV is its ability to cause co-infection with the human Address Correspondence to these authors at the Department of Chemistry, Faculty of Natural Sciences, University of Oriente, Patricio Lumumba s/n, 90500 Santiago de Cuba, Cuba. Fax: +351 220402659 (ASP) E-mail: alejspivanovich@gmail.com and REQUIMTE/Department of Chemistry and Biochemistry, University of Porto, 4169-007 Porto, Portugal. Fax: +351 220402659 (MNDSC) E-mail: ncordeir@fc.up.pt immunodeficiency virus (HIV) [6], constituting that an im- portant cause of mortality in immunocompromised patients. Nowadays, it is very difficult to treat HC. The current treatment is a combination of pegylated interferon-alpha-2a [7] (can be used also pegylated interferon-alpha-2b) and the anti-viral drug ribavirin for a period of 24 or 48 weeks, de- pending on hepatitis C virus genotype [8-11]. Interferon al- pha-2a is a protein which is released by lymphocytes in re- sponse to the presence of pathogens —such as viruses, bacte- ria, or parasites— or tumor cells (Fig. 1). It is one of the pro- teins which allows communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors. In its pegylated form (40 kDa; com- mercial name Pegasys) is an anti-viral drug discovered at the pharmaceutical company F. Hoffmann-La Roche; it has a dual mode of action - both anti-viral and on the immune sys- tem. The addition of polyethylene glycol to the interferon, through a process known as pegylation, enhances the half- life of the interferon when compared to its native form. Fig. (1). Secondary structure of interferon-alpha-2a.