Abstract
Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.
Highlights
Established in 1983 as the causative agent of the acquired immune deficiency syndrome (AIDS) (BarreSinoussi et al 1983), the human immunodeficiency virus (HIV) remains a worldwide health care issue
Computational methods are an important part of the drug design process and this kind of modelling is often denoted as computer-aided drug design (CADD)
13 inhibitors act against it, including the very first drug used in HIV treatment, the nucleoside reverse transcriptase (RT) inhibitor (NRTI) zidovudine (AZT) (Retrovir®) (Esposito et al 2012)
Summary
Established in 1983 as the causative agent of the acquired immune deficiency syndrome (AIDS) (BarreSinoussi et al 1983), the human immunodeficiency virus (HIV) remains a worldwide health care issue. It is noteworthy that some approved drugs for the treatment of an assortment of diseases owe their discovery in part to CADD methods [recently reviewed by Sliwoski et al (2014)]. This group includes anti-HIV drugs such as protease inhibitors saquinavir (Invirase®), ritonavir (Norvir®) and indinavir (Crixivan®), integrase inhibitor raltegravir (Isentress®), reverse transcriptase (RT) inhibitor rilpivirine (RPV) (Edurant®) and fusion inhibitor enfuvirtide (Fuzeon®). All the commercially available RT-targeting drugs affect the polymerase activity inhibiting its function, some RNase H inhibitors have recently been designed and studied (Tramontano & Di Santo 2010, Distinto et al 2013) (Steitz 1999, Tuske et al 2004)
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