Emphasizing the structural and computational characterisation of an HIV-1 IN binding interface against potential inhibitors for a promising drug strategy

HIV/AIDS has remained a deadly and incurable human disease. The current strand transfer inhibitors (INSTIs), such as raltegravir (RAL), face drawbacks, including a low genetic barrier to resistance and potential cross-resistance. The design of small-molecule antivirals targeting the integration step of the viral life cycle has been the recent highlight of the IN allosteric inhibitor (INLAIs) strategy. This interventive approach has been potentiated by recently developed chromane-functionalised compounds: BDM-2/INH1, MUT871/INH2, and MUT872/INH3, which exhibit therapeutic activity at the IN interface. Therefore, we investigated the conformational changes of HIV-IN and the dynamical events underlying the antiviral mechanism of the compounds upon binding to the IN allosteric interface using an integrated all-atom molecular dynamics simulation. Time-scale dynamical findings showed that the compounds induced structural changes in the protein. Moreover, the inhibitor-bound systems showed insignificant differences in the structural flexibility (mean RMSF, Å: 1.50, 1.50, 1.60, 1.30, 1.40) and the atomistic motion (mean RMSD, Å: 2.57, 2.28, 2.23, 2.33, 2.56) compared to the unbound protein within the conformational space, respectively. Trajectory investigations into the binding site indicate that compounds INH1 (–25.27 kcal/mol) and INH3 (–25.26 kcal/mol) exhibited mechanistic transitions within the interface, as evident in their high-energy interactions at the allosteric binding site. Thus, the proposed inhibitors are comparable to RAL (–27.50 kcal/mol), except for INH2 (–13.19 kcal/mol). These findings present a model that describes the structural behaviour and the mechanism by which INLAI inhibitors can interact with IN to enhance their development during clinical trials.