Raltegravir flexibility and its impact on recognition by the HIV‐1 IN targets

HIV‐1 IN is a pertinent target for the development of AIDS chemotherapy. The first IN‐specific inhibitor approved for the treatment of HIV/AIDS, RAL, was designed to block the ST reaction. We characterized the structural and conformational features of RAL and its recognition by putative HIV‐1 targets – the unbound IN, the vDNA, and the IN?vDNA complex – mimicking the IN states over the integration process. RAL binding to the targets was studied by performing an extensive sampling of the inhibitor conformational landscape and by using four different docking algorithms: Glide, Autodock, VINA, and SurFlex. The obtained data evidenced that: (i) a large binding pocket delineated by the active site and an extended loop in the unbound IN accommodates RAL in distinct conformational states all lacking specific interactions with the target; (ii) a well‐defined cavity formed by the active site, the vDNA, and the shortened loop in the IN?vDNA complex provide a more optimized inhibitor binding site in which RAL chelates Mg²⁺ cations; (iii) a specific recognition between RAL and the unpaired cytosine of the processed DNA is governed by a pair of strong H‐bonds similar to those observed in DNA base pair G‐C. The identified RAL pose at the cleaved vDNA shed light on a putative step of RAL inhibition mechanism. This modeling study indicates that the inhibition process may include as a first step RAL recognition by the processed vDNA bound to a transient intermediate IN state, and thus provides a potentially promising route to the design of IN inhibitors with improved affinity and selectivity. Copyright © 2013 John Wiley & Sons, Ltd.