Extracting functional groups of ALLINI to design derivatives of FDA‐approved drugs: Inhibition of HIV‐1 integrase

Abstract

HIV-1 integrase (IN) is crucial for integration of viral DNA into the host genome and a promising target in development of antiretroviral inhibitors. In this work, six new compounds were designed by linking the structures of two different class of HIV-1 IN inhibitors (active site binders and allosteric IN inhibitors (ALLINIs)). Among newly designed compounds, INRAT10b was found most potent HIV-1 IN inhibitor considering different docking results. To further validate protein-ligand interactions obtained from dockings, molecular dynamics simulations were performed for inhibitor raltegravir and INRAT10b placed either at active site or allosteric site of HIV-1 IN (monomer or dimer). Results suggest that both raltegravir and INRAT10b were interacting with residue Gln62, Gly140, Ile141, and Ser147. However, INRAT10b interacts better with high H-bond occupancy, which can explain the strong binding affinity of INRAT10b than raltegravir with the HIV-1 IN protein. Subdomains rearrangements in HIV-1 IN suggest that the C-terminal and catalytic core domains develop their closeness in the presence of ligand. More significantly, the newly designed derivatives represent novel compounds targeting catalytic site and C-terminal (protein-protein interaction) domains simultaneously. And we also propose INRAT10b as a promising lead compound for the development of potent HIV-1 IN inhibitors.