Virtual Screening for Potential Substances for the Prophylaxis of HIV Infection in Libraries of Commercially Available Organic Compounds

Lagunin, A. A.; Filimonov, D. A.; Gloriozova, T. A.; Tarasova, O. A.; Zakharov, A. V.; Guasch, L.; Nicklaus, M. C.; Poroikov, V. V.
October 2013
Pharmaceutical Chemistry Journal;Oct2013, Vol. 47 Issue 7, p343
Academic Journal
The search for new substances for the treatment and prophylaxis of HIV-AIDS remains relevant despite advances in highly active antiretroviral therapy (HAART), both because of the appearance of resistance to existing agents and because of their side effects and toxicity. Preventing the spread of HIV infection via sexual contacts by treating the uninfected partner has some advantage, as prophylactic effects can be obtained using simpler treatment (for example, using one agent rather than combinations of three drugs), as the need is to block the transfer of small numbers of infective virions. On the other hand, agents acting on the uninfected partner must be relatively nontoxic as they have to be used for long periods of time in healthy people. Effective chemoprophylaxis can be obtained using agents blocking the life cycle of the virus before integration into the human genome. Two widely used classes of agent therefore have potential – non-nucleoside reverse transcriptase (RT) inhibitors and integrase (IN) strand transfer inhibitors. In addition, proteins such as CD4, gp120, CCR5, CXCR4, and gp41 can be regarded as potential targets, as their functional roles at different stages in the interaction between virion and host cell have been established. As it is now known that all antiretroviral agents approved for medical use induce resistant viral strains, new anti-HIV agents must have chemical structures which are significantly different from known drugs and (if possible) must act on multiple pharmacological targets. Candidates can be sought by virtual screening of libraries of commercially available samples of chemical compounds; such libraries currently contain several million structural formulas for compounds which have been synthesized and are available for biological testing. Virtual screening can be performed using the computer programs PASS and PharmaExpert, allowing identification of substances with potential for experimental studies on the basis of a number of prognostic criteria (presence of the required types of activity, absence of side and toxic effects, appropriate physicochemical properties).We present here data on the current state of the search for new agents for the treatment and prophylaxis of HIV/AIDS, our approach to virtual screening for new potential substances for the prophylaxis of HIV/AIDS, and the results of using this approach in databases of chemical compounds available for screening. The potential for detection of anti-HIV compounds acting on multiple pharmacological targets among substances which have already been synthesized is discussed. We conclude that there is potential for the rational design of such drugs using computerized drug construction methods.


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