Виртуальный скрининг в библиотеках коммерчески доступных органических соединений потенциальных средств для профилактики ВИЧ-инфекции

Abstract

In spite of the great success of the anti-HIV drug combination therapy known as HAART (highly active antiretroviral therapy) in the treatment of HIV/AIDS, the search for new anti-HIV agents is still a worthwhile goal because of the challenges posed by viral resistance developing toward, and adverse and toxic effect of, existing therapeutics. Prevention of the infection with HIV via sexual transmission in the first place by treatment of the uninfected partner has the advantage that a simpler therapy (with, for example, one drug instead of several) could still be effective in reducing the spread of the virus. This is because, in most cases, it is only necessary to block a single infectious virion instead of combating a large number of viruses already established in the body in diverse reservoirs, and with many genetic mutations present. On the other hand, the drug(s) for treating the uninfected partner should be relatively nontoxic because of the long-term regimen of treating a healthy person. Especially for chemoprevention, it is preferable to use a drug that blocks the viral life cycle before the provirus is integrated into the host genome. Therefore, two widely used classes of anti-HIV drugs may be advantageous: reverse transcriptase inhibitors (RTI) and integrase strand transfer inhibitors (INSTI). Other proteins as CD4, gp120, CCR5, CXCR4, and gp41 are however also considered as possible targets because of their important functions during the early stages of virion interaction with the host cell. Since treatment with any of the available anti-HIV drugs selects for resistant viruses, a drug that would be used to block the transmission of the virus should be different enough from the drugs used to treat infected individuals, and should ideally be capable (if possible) to interact with several pharmacological targets. Searching for such candidates can be performed by computational virtual screening in libraries of commercially available chemical compounds, which comprise millions of samples that can be obtained for biological testing. Virtual screening can be carried out by application of computer programs such as PASS and PharmaExpert, which allows for the selecting of substances using a number of criteria (presence of the required activities, absence of adverse and toxic effects, appropriate physico-chemical properties). We present current trends in the search for new anti-HIV agents that can be used for treatment and prevention of HIV infection, a proposed novel approach for virtual screening of new agents for prophylactics of HIV/AIDS, and the results of this approach’s application to libraries of compounds available for screening. We analyzed the possibilities of identification of compounds acting on several pharmacological targets among existing substances. We come to the conclusion that rational design of such compounds de novo using computer-aided drug design approaches seems more promising.