ChemBioChem · 2015 · 47 citations · 20 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryMolecular VirologyAntiretroviral TherapyEnzyme InhibitionLigand BindingMolecular DockingProtein-ligand BindingVirtual ScreeningActive Site InhibitorsAllosteric BindingAllosteric Drug DiscoveryAllosteric Ligand BindingAllosteric Ligand DiscoveryBinder IdentificationMolecular Docking Of InhibitorsStructure-based Allosteric Drug Design
HIV-1 integrase (IN) active site inhibitors are the latest class of drugs approved for HIV treatment. The selection of IN strand-transfer drug-resistant HIV strains in patients supports the development of new agents that are active as allosteric IN inhibitors. Here, a docking-based virtual screening has been applied to a small library of natural ligands to identify new allosteric IN inhibitors that target the sucrose binding pocket. From theoretical studies, kuwanon-L emerged as the most promising binder and was thus selected for biological studies. Biochemical studies showed that kuwanon-L is able to inhibit the HIV-1 IN catalytic activity in the absence and in the presence of LEDGF/p75 protein, the IN dimerization, and the IN/LEDGF binding. Kuwanon-L also inhibited HIV-1 replication in cell cultures. Overall, docking and biochemical results suggest that kuwanon-L binds to an allosteric binding pocket and can be considered an attractive lead for the development of new allosteric IN antiviral agents.
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Development and testing of a general amber force field
Junmei Wang, Romain M. Wolf, James W. Caldwell et al. · Journal of Computational Chemistry · 2004 · 19.6K citations