Use of virtual screening for discovering antiretroviral compounds interacting with the HIV-1 nucleocapsid protein

The HIV-1 nucleocapsid protein (NC) is considered as an emerging drug target for the therapy of AIDS. Several studies have highlighted the crucial role of NC within the viral replication cycle. However, although NC inhibition has provided in vitro and in vivo antiretroviral activity, drug-candidates which interfere with NC functions are still missing in the therapeutic arsenal against HIV. Based on previous studies, where the dynamic behavior of NC and its ligand binding properties have been investigated by means of computational methods, here we used a virtual screening protocol for discovering novel antiretroviral compounds which interact with NC. The antiretroviral activity of virtual hits was tested in vitro, whereas biophysical studies elucidated the direct interaction of most active compounds with NC(11–55), a peptide corresponding to the zinc finger domain of NC. Two novel antiretroviral small molecules capable of interacting with NC are presented here.

► We performed a structure-based virtual screening for identifying HIV-1 NC inhibitors. ► Two small molecules showed concentration-dependent antiviral activity on infected cells. ► Biophysical studies showed that these small molecules bind on NC(12–55). ► Docking simulations suggested possible binding modes in line with experimental data. ► Antiretroviral compounds here discovered support the druggability of NC.