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

Abstract

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 Mg(2+) 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.

The HIV-1 Integrase: Modeling and Beyond

“…A slight preference for the Z-configuration of carbonylamino-hydroxypyrimidinonepharmacophore in the gas phase was observed, in coherence with the established predisposition of β-ketoenols -a principle corner stone of this pharmacophore -to adopt the Z-isomer in the solid state (Figure 9 b) [78][79][80]. The preference of aliphatic β-ketoenols to form energetically favorable Z-configurartion has been predicted early by ab initio studies at the B3LYP/3-G** level of theory [81].…”

“…To explore the role of the HIV-1 viral DNA in RAL recognition we docked RAL onto the non-cleaved and cleaved DNA (the terminal GT nucleotides were removed) [79]. We found that RAL docked onto the non-cleaved vDNA is positioned in the minor groove of the substrate.…”

A computational overview of integrase strand transfer inhibitors (INSTIs) against emerging and evolving drug-resistant HIV-1 integrase mutants

“…This complex then integrates with the host’s cellular genome with the aid of lens epithelial-derived growth factor (LEDGF or p75) in the second step called strand transfer (ST), infecting the individual (Varadarajan et al 2013 ; Park et al 2021 ). Both these reactions are energetically independent as well as set apart, both spatially and temporally as the 3’P occurs in the cytoplasm of the infected cells, whereas the ST activity takes place in the nuclei (Arora et al 2013 ). Once integrated, it is now referred to as a provirus, which acts as a post-integrative template for viral infection, allowing its self-transcription to release more infectious copies of itself (Thierry et al 2017 ).…”

“…This domain also encompasses a flexible 10 residues loop (140–149) that is adjacent to the catalytic site, involved in vcDNA substrate recognition. Residues 213–288: C-terminal domain (CTD) This region serves as a non-specific binding site for the vcDNA and further contributes to stabilizing the IN–vcDNA complex (Arora et al 2013 ; Ross 2015 ; Thierry et al 2017 ; Nusrath Unissa et al 2017 ; Zhou et al 2021 ). …”

“…This region serves as a non-specific binding site for the vcDNA and further contributes to stabilizing the IN–vcDNA complex (Arora et al 2013 ; Ross 2015 ; Thierry et al 2017 ; Nusrath Unissa et al 2017 ; Zhou et al 2021 ).…”