The State of the Science: A 5 - Year Review on the Computer - Aided Design for Global Anti - AIDS Drug Development

Abstract

Since acquired immune deficiency syndrome (AIDS) was recognized by the U.S. centers for disease control and prevention in 1981 (Gallo, 2006), a large number of patients have died due to human immunodeficiency virus (HIV) related causes. In 2009, there were an estimated 33.3 million (31.4 million-35.3 million) persons living with HIV, 2.6 million (2.3 million-2.8 million) persons newly infected by HIV, and 1.8 million (1.6 million-2.1 million) dying due to AIDS. Research on vaccines is one of several strategies to reduce the worldwide harm from AIDS, however, these are early results, and have either not been developed to the point of human testing, or not been fully peer reviewed and replicated by other teams (Girard et al., 2006). Thus, the AIDS patient’s treatment continues to focus on seeking the chemical anti-HIV agents. The current anti-HIV drugs approved by Food and Drug Administration (FDA) belong to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), fusion inhibitors (FIs) and entry inhibitors. The highly active antiretroviral therapy (HAART), which combines over three drugs, has dramatically improved the quality of patients' life (Barbaro et al., 2005; Gulick et al., 2003; Hammer et al., 1996). Three drugs are used together in order to reduce the likelihood of resistance. However, the therapeutic effect is confined by the side effects and toxicity due to long-term use, and the emergence of drug-resistant (Louie & Markowitz, 2002). The multiple steps of HIV replication cycle present novel therapeutic targets other than reverse transcriptase (RT) and protease (PT) for drug development (Greene, 2004; Tan et al., 2010) (Fig. 1). Continued efforts have been made on discovering new inhibitors that target not only RT, PT, IN and the transmembrane glycoprotein gp41, but also other viral targets, achievements on which have been reviewed comprehensively in literatures (Citterio &