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Development of novel therapeutics for treatment of HIV infections is a very challenging process due to the high rate of viral mutation. On this basis, inhibition of more than one HIV replication pathway is a potential efficient way to obtain control over the HIV progression. In the present study we have performed computational analyses in order to investigate the dual inhibitory action of a set of diketo derivatives (carboxylic acid and esters) against RNase H (RNH) and integrase (IN). Docking studies performed with these compounds revealed that the interaction between the ligands and magnesium ions and the surrounding amino acids/water within the protein are important for the dual inhibitory activity of these compounds. Moreover, from a binding mode analysis, the carboxylic acid (series 8) and ester (series 7) derivatives showed distinct binding patterns in RNH and IN, meaning that all compounds bind with magnesium ions through oxygen atoms of the ligands (either enol or carboxylate); however, the orientation of the hydrophobic tail of the ligand is quite different in both systems. Additional validation using a small dataset also strengthens this binding mode hypothesis. The results reported here could be useful for design or screening of small molecules against IN and RNH activity for the development of effective drugs for HIV treatment.

Dual mechanism of HIV-1 integrase and RNase H inhibition by diketo derivatives – a computational study